Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same

ABSTRACT

Provided are 4′-arylmethoxy isoindoline compounds, and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.

This application claims priority to U.S. Provisional Application No.61/303,618, filed Feb. 11, 2010, the entirety of which is incorporatedherein by reference.

1. FIELD

Provided herein are 4′-arylmethoxy isoindoline derivatives.Pharmaceutical compositions comprising the compounds and methods fortreating, preventing and managing various disorders using the compoundsand compositions are also disclosed.

2. BACKGROUND

2.1 Pathobiology of Cancer and Other Diseases

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia. Theneoplastic lesion may evolve clonally and develop an increasing capacityfor invasion, growth, metastasis, and heterogeneity, especially underconditions in which the neoplastic cells escape the host's immunesurveillance. Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

There is an enormous variety of cancers which are described in detail inthe medical literature. Examples include cancer of the lung, colon,rectum, prostate, breast, brain, and intestine. The incidence of cancercontinues to climb as the general population ages, as new cancersdevelop, and as susceptible populations (e.g., people infected with AIDSor excessively exposed to sunlight) grow. However, options for thetreatment of cancer are limited. For example, in the case of bloodcancers (e.g., multiple myeloma), few treatment options are available,especially when conventional chemotherapy fails and bone-marrowtransplantation is not an option. A tremendous demand therefore existsfor new methods and compositions that can be used to treat patients withcancer.

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. The most direct ofthese mechanisms is the secretion by the tumor cells of cytokines withangiogenic properties. Examples of these cytokines include acidic andbasic fibroblastic growth factor (a,b-FGF), angiogenin, vascularendothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cellscan release angiogenic peptides through the production of proteases andthe subsequent breakdown of the extracellular matrix where somecytokines are stored (e.g., b-FGF). Angiogenesis can also be inducedindirectly through the recruitment of inflammatory cells (particularlymacrophages) and their subsequent release of angiogenic cytokines (e.g.,TNF-α, b-FGF).

A variety of other diseases and disorders are also associated with, orcharacterized by, undesired angiogenesis. For example, enhanced orunregulated angiogenesis has been implicated in a number of diseases andmedical conditions including, but not limited to, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,rubeosis (neovascularization of the angle), viral diseases, geneticdiseases, inflammatory diseases, allergic diseases, and autoimmunediseases. Examples of such diseases and conditions include, but are notlimited to: diabetic retinopathy; retinopathy of prematurity; cornealgraft rejection; neovascular glaucoma; retrolental fibroplasia;arthritis; and proliferative vitreoretinopathy.

Accordingly, compounds that can control angiogenesis or inhibit theproduction of certain cytokines, including TNF-α, may be useful in thetreatment and prevention of various diseases and conditions.

2.2 Methods of Treating Cancer

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, e.g., Stockdale, 1998, Medicine, vol. 3, Rubenstein andFederman, eds., Chapter 12, Section IV). Recently, cancer therapy couldalso involve biological therapy or immunotherapy. All of theseapproaches pose significant drawbacks for the patient. Surgery, forexample, may be contraindicated due to the health or age of a patient ormay be unacceptable to the patient.

Additionally, surgery may not completely remove neoplastic tissue.Radiation therapy is only effective when the neoplastic tissue exhibitsa higher sensitivity to radiation than normal tissue. Radiation therapycan also often elicit serious side effects. Hormonal therapy is rarelygiven as a single agent. Although hormonal therapy can be effective, itis often used to prevent or delay recurrence of cancer after othertreatments have removed the majority of cancer cells. Biologicaltherapies and immunotherapies are limited in number and may produce sideeffects such as rashes or swellings, flu-like symptoms, including fever,chills and fatigue, digestive tract problems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of cancer. A majority of cancerchemotherapeutics act by inhibiting DNA synthesis, either directly, orindirectly by inhibiting the biosynthesis of deoxyribonucleotidetriphosphate precursors, to prevent DNA replication and concomitant celldivision. Gilman et al., Goodman and Gilman's: The Pharmacological Basisof Therapeutics, Tenth Ed. (McGraw Hill, New York).

Despite availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubensteinand Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeuticagents are toxic, and chemotherapy causes significant, and oftendangerous side effects including severe nausea, bone marrow depression,and immunosuppression. Additionally, even with administration ofcombinations of chemotherapeutic agents, many tumor cells are resistantor develop resistance to the chemotherapeutic agents. In fact, thosecells resistant to the particular chemotherapeutic agents used in thetreatment protocol often prove to be resistant to other drugs, even ifthose agents act by different mechanism from those of the drugs used inthe specific treatment. This phenomenon is referred to as pleiotropicdrug or multidrug resistance. Because of the drug resistance, manycancers prove or become refractory to standard chemotherapeutictreatment protocols.

Other diseases or conditions associated with, or characterized by,undesired angiogenesis are also difficult to treat. However, somecompounds such as protamine, hepain and steroids have been proposed tobe useful in the treatment of certain specific diseases. Taylor et al.,Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S.Pat. Nos. 5,001,116 and 4,994,443.

Still, there is a significant need for safe and effective methods oftreating, preventing and managing cancer and other diseases andconditions, including for diseases that are refractory to standardtreatments, such as surgery, radiation therapy, chemotherapy andhormonal therapy, while reducing or avoiding the toxicities and/or sideeffects associated with the conventional therapies.

3. SUMMARY

Provided herein are 4′-arylmethoxy isoindoline compounds, andpharmaceutically acceptable salts, solvates (e.g., hydrates), prodrugs,clathrates, or stereoisomers thereof.

Also provided are methods of treating and managing various diseases ordisorders. The methods comprise administering to a patient in need ofsuch treatment or management a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable salt,solvate, prodrug, clathrate, or stereoisomer thereof.

Further provided are methods of preventing various diseases anddisorders, which comprise administering to a patient in need of suchprevention a prophylactically effective amount of a compound providedherein, or a pharmaceutically acceptable salt, solvate, prodrug,clathrate, or stereoisomer thereof.

Also provided herein are pharmaceutical compositions, single unit dosageforms, dosing regimens and kits which comprise a compound providedherein, or a pharmaceutically acceptable salt, solvate, prodrug,clathrate, or stereoisomer thereof.

4. DETAILED DESCRIPTION

In one embodiment, provided are isoindoline compounds, andpharmaceutically acceptable salts, solvates, prodrugs, clathrate, andstereoisomers thereof.

In another embodiment, provided are methods of treating, managing, andpreventing various diseases and disorders, which comprises administeringto a patient in need of such treatment or prevention a therapeuticallyor prophylactically effective amount of a compound provided herein, or apharmaceutically acceptable salt, solvate, prodrug, clathrate, orstereoisomer thereof. Examples of diseases and disorders are describedherein.

In other embodiments, a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, prodrug, clathrate, or stereoisomer thereof,is administered in combination with another drug (“second active agent”)or treatment. Second active agents include small molecules and largemolecules (e.g., proteins and antibodies), examples of which areprovided herein, as well as stem cells. Methods, or therapies, that canbe used in combination with the administration of compounds providedherein include, but are not limited to, surgery, blood transfusions,immunotherapy, biological therapy, radiation therapy, and other non-drugbased therapies presently used to treat, prevent or manage variousdisorders described herein.

Also provided are pharmaceutical compositions (e.g., single unit dosageforms) that can be used in the methods provided herein. In oneembodiment, pharmaceutical compositions comprise a compound providedherein, or a pharmaceutically acceptable salt, solvate, prodrug,clathrate, or stereoisomer thereof, and optionally a second activeagent.

4.1 Compounds

In one embodiment, provided herein is a compound of formula (I):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein:

-   X is C═O or CH₂;-   R¹ is —Y—R³;-   R² is H or (C₁-C₆)alkyl;-   Y is: 6 to 10 membered aryl, heteroaryl or heterocycle, each of    which may be optionally substituted with one or more halogen; or a    bond;-   R³ is: —(CH₂)_(n)-aryl, —O—(CH₂)_(n)-aryl or —(CH₂)_(n)—O-aryl,    wherein the aryl is optionally substituted with one or more:    (C₁-C₆)alkyl, itself optionally substituted with one or more    halogen; (C₁-C₆)alkoxy, itself substituted with one or more halogen;    oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10    membered aryl or heteroaryl, optionally substituted with one or more    (C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen; —CONH₂; or    —COO—(C₁-C₆)alkyl, wherein the alkyl may be optionally substituted    with one or more halogen;    -   —(CH₂)_(n)-heterocycle, —O—(CH₂)_(n)-heterocycle or        —(CH₂)_(n)—O-heterocycle, wherein the heterocycle is optionally        substituted with one or more: (C₁-C₆)alkyl, itself optionally        substituted with one or more halogen; (C₁-C₆)alkoxy, itself        substituted with one or more halogen; oxo; amino; carboxyl;        cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or        heteroaryl, optionally substituted with one or more        (C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen; —CONH₂; or        —COO—(C₁-C₆)alkyl, wherein the alkyl may be optionally        substituted with one or more halogen; or    -   —(CH₂)_(n)-heteroaryl, —O—(CH₂)_(n)-heteroaryl or        —(CH₂)_(n)—O-heteroaryl, wherein the heteroaryl is optionally        substituted with one or more: (C₁-C₆)alkyl, itself optionally        substituted with one or more halogen; (C₁-C₆)alkoxy, itself        substituted with one or more halogen; oxo; amino; carboxyl;        cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or        heteroaryl, optionally substituted with one or more        (C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen; —CONH₂; or        —COO—(C₁-C₆)alkyl, wherein the alkyl may be optionally        substituted with one or more halogen; and-   n is 0, 1, 2 or 3.

In one embodiment, X is C═O. In another embodiment, C is CH₂.

In one embodiment, R² is H. In another embodiment, R² is (C₁-C₆)alkyl.

In one embodiment, Y is aryl. In another embodiment, Y is heteroaryl. Inanother embodiment, Y is heterocycle. In another embodiment, Y is abond.

In one embodiment, R³ is unsubstituted —(CH₂)_(n)-aryl. In anotherembodiment, R³ is —(CH₂)_(n)-aryl substituted with one or more(C₁-C₆)alkyl, itself optionally substituted with one or more halogen. Inanother embodiment, R³ is —(CH₂)_(n)-aryl substituted with one or more(C₁-C₆)alkoxy, itself substituted with one or more halogen. In anotherembodiment, R³ is —(CH₂)_(n)-aryl substituted with one or more oxo. Inanother embodiment, R³ is —(CH₂)_(n)-aryl substituted with one or moreamino. In another embodiment, R³ is —(CH₂)_(n)-aryl substituted with oneor more carboxyl. In another embodiment, R³ is —(CH₂)_(n)-arylsubstituted with one or more cyano. In another embodiment, R³ is—(CH₂)_(n)-aryl substituted with one or more hydroxyl. In anotherembodiment, R³ is —(CH₂)_(n)-aryl substituted with one or more halogen.In another embodiment, R³ is —(CH₂)_(n)-aryl substituted with one ormore deuterium. In another embodiment, R³ is —(CH₂)_(n)-aryl substitutedwith one or more 6 to 10 membered aryl, optionally substituted with oneor more (C₁-C₆)alkyl. In another embodiment, R³ is —(CH₂)_(n)-arylsubstituted with one or more 6 to 10 membered heteroaryl, optionallysubstituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen. Inanother embodiment, R³ is —(CH₂)_(n)-aryl substituted with one or more—CONH₂. In another embodiment, R³ is —(CH₂)_(n)-aryl substituted withone or more —COO—(C₁-C₆)alkyl, wherein the alkyl may be optionallysubstituted with one or more halogen.

In one embodiment, R³ is unsubstituted —O—(CH₂)_(n)-aryl. In anotherembodiment, R³ is —O—(CH₂)_(n)-aryl substituted with one or more(C₁-C₆)alkyl, itself optionally substituted with one or more halogen. Inanother embodiment, R³ is —O—(CH₂)_(n)-aryl substituted with one or more(C₁-C₆)alkoxy, itself substituted with one or more halogen. In anotherembodiment, R³ is —O—(CH₂)_(n)-aryl substituted with one or more oxo. Inanother embodiment, R³ is —O—(CH₂)_(n)-aryl substituted with one or moreamino. In another embodiment, R³ is —O—(CH₂)_(n)-aryl substituted withone or more carboxyl. In another embodiment, R³ is —O—(CH₂)_(n)-arylsubstituted with one or more cyano. In another embodiment, R³ is—O—(CH₂)_(n)-aryl substituted with one or more hydroxyl. In anotherembodiment, R³ is —O—(CH₂)_(n)-aryl substituted with one or morehalogen. In another embodiment, R³ is —O—(CH₂)_(n)-aryl substituted withone or more deuterium. In another embodiment, R³ is —O—(CH₂)_(n)-arylsubstituted with one or more 6 to 10 membered aryl, optionallysubstituted with one or more (C₁-C₆)alkyl. In another embodiment, R³ is—O—(CH₂)_(n)-aryl substituted with one or more 6 to 10 memberedheteroaryl, optionally substituted with one or more (C₁-C₆)alkyl,(C₁-C₆)alkoxy or halogen. In another embodiment, R³ is —O—(CH₂)_(n)-arylsubstituted with one or more —CONH₂. In another embodiment, R³ is—O—(CH₂)_(n)-aryl substituted with one or more —COO—(C₁-C₆)alkyl,wherein the alkyl may be optionally substituted with one or morehalogen.

In one embodiment, R³ is unsubstituted —(CH₂)_(n)—O-aryl. In anotherembodiment, R³ is —(CH₂)_(n)—O-aryl substituted with one or more(C₁-C₆)alkyl, itself optionally substituted with one or more halogen. Inanother embodiment, R³ is —(CH₂)_(n)—O-aryl substituted with one or more(C₁-C₆)alkoxy, itself substituted with one or more halogen. In anotherembodiment, R³ is —(CH₂)_(n)—O-aryl substituted with one or more oxo. Inanother embodiment, R³ is —(CH₂)_(n)—O-aryl substituted with one or moreamino. In another embodiment, R³ is —(CH₂)_(n)—O-aryl substituted withone or more carboxyl. In another embodiment, R³ is —(CH₂)_(n)—O-arylsubstituted with one or more cyano. In another embodiment, R³ is—(CH₂)—O-aryl substituted with one or more hydroxyl. In anotherembodiment, R³ is —(CH₂)_(n)—O-aryl substituted with one or morehalogen. In another embodiment, R³ is —(CH₂)_(n)—O-aryl substituted withone or more deuterium. In another embodiment, R³ is —(CH₂)_(n)—O-arylsubstituted with one or more 6 to 10 membered aryl, optionallysubstituted with one or more (C₁-C₆)alkyl. In another embodiment, R³ is—(CH₂)—O-aryl substituted with one or more 6 to 10 membered heteroaryl,optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkoxy orhalogen. In another embodiment, R³ is —(CH₂)_(n)—O-aryl substituted withone or more —CONH₂. In another embodiment, R³ is —(CH₂)_(n)—O-arylsubstituted with one or more —COO—(C₁-C₆)alkyl, wherein the alkyl may beoptionally substituted with one or more halogen.

In one embodiment, R³ is unsubstituted —(CH₂)_(n)-heterocycle. Inanother embodiment, R³ is —(CH₂)_(n)-heterocycle substituted with one ormore (C₁-C₆)alkyl, itself optionally substituted with one or morehalogen. In another embodiment, R³ is —(CH₂)_(n)-heterocycle substitutedwith one or more (C₁-C₆)alkoxy, itself substituted with one or morehalogen. In another embodiment, R³ is —(CH₂)_(n)-heterocycle substitutedwith one or more oxo. In another embodiment, R³ is—(CH₂)_(n)-heterocycle substituted with one or more amino. In anotherembodiment, R³ is —(CH₂)_(n)-heterocycle substituted with one or morecarboxyl. In another embodiment, R³ is —(CH₂)_(n)-heterocyclesubstituted with one or more cyano. In another embodiment, R³ is—(CH₂)_(n)-heterocycle substituted with one or more hydroxyl. In anotherembodiment, R³ is —(CH₂)_(n)-heterocycle substituted with one or morehalogen. In another embodiment, R³ is —(CH₂)_(n)-heterocycle substitutedwith one or more deuterium. In another embodiment, R³ is—(CH₂)_(n)-heterocycle substituted with one or more 6 to 10 memberedaryl, optionally substituted with one or more (C₁-C₆)alkyl. In anotherembodiment, R³ is —(CH₂)_(n)-heterocycle substituted with one or more 6to 10 membered heteroaryl, optionally substituted with one or more(C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen. In another embodiment, R³ is—(CH₂)_(n)-heterocycle substituted with one or more —CONH₂. In anotherembodiment, R³ is —(CH₂)_(n)-heterocycle substituted with one or more—COO—(C₁-C₆)alkyl, wherein the alkyl may be optionally substituted withone or more halogen.

In one embodiment, R³ is unsubstituted —O—(CH₂)_(n)-heterocycle. Inanother embodiment, R³ is —O—(CH₂)_(n)-heterocycle substituted with oneor more (C₁-C₆)alkyl, itself optionally substituted with one or morehalogen. In another embodiment, R³ is —O—(CH₂)_(n)-heterocyclesubstituted with one or more (C₁-C₆)alkoxy, itself substituted with oneor more halogen. In another embodiment, R³ is —O—(CH₂)_(n)-heterocyclesubstituted with one or more oxo. In another embodiment, R³ is—O—(CH₂)_(n)-heterocycle substituted with one or more amino. In anotherembodiment, R³ is —O—(CH₂)_(n)-heterocycle substituted with one or morecarboxyl. In another embodiment, R³ is —O—(CH₂)_(n)-heterocyclesubstituted with one or more cyano. In another embodiment, R³ is—O—(CH₂)_(n)-heterocycle substituted with one or more hydroxyl. Inanother embodiment, R³ is —O—(CH₂)_(n)-heterocycle substituted with oneor more halogen. In another embodiment, R³ is —O—(CH₂)_(n)-heterocyclesubstituted with one or more deuterium. In another embodiment, R³ is—O—(CH₂)_(n)-heterocycle substituted with one or more 6 to 10 memberedaryl, optionally substituted with one or more (C₁-C₆)alkyl. In anotherembodiment, R³ is —O—(CH₂)_(n)-heterocycle substituted with one or more6 to 10 membered heteroaryl, optionally substituted with one or more(C₁-C₆)alkyl; (C₁-C₆)alkoxy or halogen. In another embodiment, R³ is—O—(CH₂)_(n)-heterocycle substituted with one or more —CONH₂. In anotherembodiment, R³ is —O—(CH₂)_(n)-heterocycle substituted with one or more—COO—(C₁-C₆)alkyl, wherein the alkyl may be optionally substituted withone or more halogen.

In one embodiment, R³ is unsubstituted —(CH₂)_(n)—O-heterocycle. Inanother embodiment, R³ is —(CH₂)_(n)—O-heterocycle substituted with oneor more (C₁-C₆)alkyl, itself optionally substituted with one or morehalogen. In another embodiment, R³ is —(CH₂)_(n)—O-heterocyclesubstituted with one or more (C₁-C₆)alkoxy, itself substituted with oneor more halogen. In another embodiment, R³ is —(CH₂)_(n)—O-heterocyclesubstituted with one or more oxo. In another embodiment, R³ is—(CH₂)_(n)—O-heterocycle substituted with one or more amino. In anotherembodiment, R³ is —(CH₂)_(n)—O-heterocycle substituted with one or morecarboxyl. In another embodiment, R³ is —(CH₂)_(n)—O-heterocyclesubstituted with one or more cyano. In another embodiment, R³ is—(CH₂)—O-heterocycle substituted with one or more hydroxyl. In anotherembodiment, R³ is —(CH₂)_(n)—O-heterocycle substituted with one or morehalogen. In another embodiment, R³ is —(CH₂)_(n)—O-heterocyclesubstituted with one or more deuterium. In another embodiment, R³ is—(CH₂)_(n)—O-heterocycle substituted with one or more 6 to 10 memberedaryl, optionally substituted with one or more (C₁-C₆)alkyl. In anotherembodiment, R³ is —(CH₂)_(n)—O-heterocycle substituted with one or more6 to 10 membered heteroaryl, optionally substituted with one or more(C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen. In another embodiment, R³ is—(CH₂)_(n)—O-heterocycle substituted with one or more —CONH₂. In anotherembodiment, R³ is —(CH₂)_(n)—O-heterocycle substituted with one or more—COO—(C₁-C₆)alkyl, wherein the alkyl may be optionally substituted withone or more halogen.

In one embodiment, R³ is unsubstituted —(CH₂)_(n)-heteroaryl. In anotherembodiment, R³ is —(CH₂)_(n)-heteroaryl substituted with one or more(C₁-C₆)alkyl, itself optionally substituted with one or more halogen. Inanother embodiment, R³ is —(CH₂)_(n)-heteroaryl substituted with one ormore (C₁-C₆)alkoxy, itself substituted with one or more halogen. Inanother embodiment, R³ is —(CH₂)_(n)-heteroaryl substituted with one ormore oxo. In another embodiment, R³ is —(CH₂)_(n)-heteroaryl substitutedwith one or more amino. In another embodiment, R³ is—(CH₂)_(n)-heteroaryl substituted with one or more carboxyl. In anotherembodiment, R³ is —(CH₂)_(n)-heteroaryl substituted with one or morecyano. In another embodiment, R³ is —(CH₂)_(n)-heteroaryl substitutedwith one or more hydroxyl. In another embodiment, R³ is—(CH₂)_(n)-heteroaryl substituted with one or more halogen. In anotherembodiment, R³ is —(CH₂)_(n)-heteroaryl substituted with one or moredeuterium. In another embodiment, R³ is —(CH₂)_(n)-heteroarylsubstituted with one or more 6 to 10 membered aryl, optionallysubstituted with one or more (C₁-C₆)alkyl. In another embodiment, R³ is—(CH₂)_(n)-heteroaryl substituted with one or more 6 to 10 memberedheteroaryl, optionally substituted with one or more (C₁-C₆)alkyl,(C₁-C₆)alkoxy or halogen. In another embodiment, R³ is—(CH₂)_(n)-heteroaryl substituted with one or more —CONH₂. In anotherembodiment, R³ is —(CH₂)_(n)-heteroaryl substituted with one or more—COO—(C₁-C₆)alkyl, wherein the alkyl may be optionally substituted withone or more halogen.

In one embodiment, R³ is unsubstituted —O—(CH₂)_(n)-heteroaryl. Inanother embodiment, R³ is —O—(CH₂)_(n)-heteroaryl substituted with oneor more (C₁-C₆)alkyl, itself optionally substituted with one or morehalogen. In another embodiment, R³ is —O—(CH₂)_(n)-heteroarylsubstituted with one or more (C₁-C₆)alkoxy, itself substituted with oneor more halogen. In another embodiment, R³ is —O—(CH₂)_(n)-heteroarylsubstituted with one or more oxo. In another embodiment, R³ is—O—(CH₂)_(n)-heteroaryl substituted with one or more amino. In anotherembodiment, R³ is —O—(CH₂)_(n)-heteroaryl substituted with one or morecarboxyl. In another embodiment, R³ is —O—(CH₂)_(n)-heteroarylsubstituted with one or more cyano. In another embodiment, R³ is—O—(CH₂)_(n)-heteroaryl substituted with one or more hydroxyl. Inanother embodiment, R³ is —O—(CH₂)_(n)-heteroaryl substituted with oneor more halogen. In another embodiment, R³ is —O—(CH₂)_(n)-heteroarylsubstituted with one or more deuterium. In another embodiment, R³ is—O—(CH₂)_(n)-heteroaryl substituted with one or more 6 to 10 memberedaryl, optionally substituted with one or more (C₁-C₆)alkyl. In anotherembodiment, R³ is —O—(CH₂)_(n)-heteroaryl substituted with one or more 6to 10 membered heteroaryl, optionally substituted with one or more(C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen. In another embodiment, R³ is—O—(CH₂)_(n)-heteroaryl substituted with one or more —CONH₂. In anotherembodiment, R³ is —O—(CH₂)_(n)-heteroaryl substituted with one or more—COO—(C₁-C₆)alkyl, wherein the alkyl may be optionally substituted withone or more halogen.

In one embodiment, R³ is unsubstituted —(CH₂)_(n)—O-heteroaryl. Inanother embodiment, R³ is —(CH₂)_(n)—O-heteroaryl substituted with oneor more (C₁-C₆)alkyl, itself optionally substituted with one or morehalogen. In another embodiment, R³ is —(CH₂)_(n)—O-heteroarylsubstituted with one or more (C₁-C₆)alkoxy, itself substituted with oneor more halogen. In another embodiment, R³ is —(CH₂)_(n)—O-heteroarylsubstituted with one or more oxo. In another embodiment, R³ is—(CH₂)_(n)—O-heteroaryl substituted with one or more amino. In anotherembodiment, R³ is —(CH₂)_(n)—O-heteroaryl substituted with one or morecarboxyl. In another embodiment, R³ is —(CH₂)_(n)—O-heteroarylsubstituted with one or more cyano. In another embodiment, R³ is—(CH₂)_(n)—O-heteroaryl substituted with one or more hydroxyl. Inanother embodiment, R³ is —(CH₂)_(n)—O-heteroaryl substituted with oneor more halogen. In another embodiment, R³ is —(CH₂)_(n)—O-heteroarylsubstituted with one or more deuterium. In another embodiment, R³ is—(CH₂)_(n)—O-heteroaryl substituted with one or more 6 to 10 memberedaryl, optionally substituted with one or more (C₁-C₆)alkyl. In anotherembodiment, R³ is —(CH₂)_(n)—O-heteroaryl substituted with one or more 6to 10 membered heteroaryl, optionally substituted with one or more(C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen. In another embodiment, R³ is—(CH₂)_(n)—O-heteroaryl substituted with one or more —CONH₂. In anotherembodiment, R³ is —(CH₂)_(n)—O-heteroaryl substituted with one or more—COO—(C₁-C₆)alkyl, wherein the alkyl may be optionally substituted withone or more halogen.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

All of the specific combinations that can result from the definitionprovided herein for X, R¹, R², Y, R³ and n are encompassed.

In one embodiment, X is CH₂.

In one embodiment, Y is aryl. In another embodiment, Y is phenyl.

In another embodiment wherein Y is phenyl, R³ is —(CH₂)_(n)-heterocycle.In one embodiment, the heterocycle is morpholinyl, piperidinyl orpyrrolidinyl.

In one embodiment, Y is a heteroaryl. In another embodiment, Y is a 10membered hetero aryl. In another embodiment, Y is benzo[d]thiazole. Inanother embodiment, Y is benzofuran. In another embodiment, Y isquinoline.

In another embodiment where Y is heteroaryl, R³ is—(CH₂)_(n)-heterocycle. In one embodiment, the heterocycle ismorpholinyl, piperidinyl or pyrrolidinyl.

In one embodiment, Y is a bond. In another embodiment where Y is a bond,R³ is —(CH₂)_(n)-heterocycle or —(CH₂)_(n)-heteroaryl.

In one embodiment, examples include, but are not limited to:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

In another embodiment, provided herein is a compound of formula (II):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein:

-   R⁴ is unsubstituted 9 to 10 membered bicyclic ring is benzothiazole,    quinoline, isoquinoline, naphthalene, 2,3-dihydro-1H-indene,    benzo[d][1,2,3]triazole, imidazo[1,2-a]pyridine, benzofuran,    2,3-dihydrobenzofuran, benzothiophene, benzo[d]oxazole isoindoline    or chroman;    with the proviso that if the bicyclic ring is benzofuran or    benzothiophene, then the ring is not connected to the isoindole ring    through the 2-position.

In one embodiment, R⁴ is benzothiazole. In another embodiment, R⁴ isquinoline. In another embodiment, R⁴ is isoquinoline. In anotherembodiment, R⁴ is naphthalene. In another embodiment, R⁴ is2,3-dihydro-1H-indene. In another embodiment, R⁴ isbenzo[d][1,2,3]triazole. In another embodiment, R⁴ isimidazo[1,2-a]pyridine. In another embodiment, R⁴ is benzofuran. Inanother embodiment, R⁴ is 2,3-dihydrobenzofuran. In another embodiment,R⁴ is benzothiophene. In another embodiment, R⁴ is benzo[d]oxazoleisoindoline. In another embodiment, R⁴ is chroman.

In one embodiment, specific examples include, but are not limited to:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

In another embodiment, provided herein is a compound of formula (III):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein:

-   X is CH₂ or C═O;-   R⁵, R⁶ and R⁷ are each independently hydrogen, halogen, nitro,    carbamoyl, amino, —SO₂R⁸, —CONR⁹R¹⁰, —(C₁-C₆)alkyl or    —(C₁-C₆)alkoxy, said alkyl or alkoxy may be optionally substituted    with one or more halogen, amino, hydroxyl, or NR⁹R¹⁰;-   R⁸ is: (C₁-C₆)alkyl, optionally substituted with (C₁-C₆)alkyl or    (C₆-C₁₀)aryl; amino, optionally substituted with (C₁-C₆)alkyl or    (C₆-C₁₀)aryl; or 6 to 10 membered heterocycle, optionally    substituted with (C₁-C₆)alkyl or (C₆-C₁₀)aryl;-   R⁹ and R¹⁰ are each independently hydrogen, 6 to 10 membered aryl,    —COO—(C₁-C₆)alkyl, —(C₀-C₆)alkyl-CHO, —(C₀-C₆)alkyl-COOH,    —(C₀-C₆)alkyl-NR^(9′)R^(10′), —(C₀-C₆)alkyl-(5 to 10 membered    heterocycle), —(C₁-C₆)alkyl-OH, —(C₁-C₆)alkyl-O—(C₁-C₆)alkyl,    (C₁-C₆)alkyl, or (C₃-C₆)cycloalkyl; or-   R⁹ and R¹⁰ together may form an optionally substituted 5 to 6    membered ring containing one or more heteroatoms; and-   R^(9′) and R^(10′) are each independently hydrogen or (C₁-C₆)alkyl;    with the proviso that all of R⁵-R⁷ cannot be hydrogen; and    with the proviso that if one of R⁵-R⁷ is hydrogen and the remaining    two of R⁵-R⁷ are both chloride, then the two chloride atoms cannot    be on 3 and 4 position of the phenyl ring.

In one embodiment, R⁵ is hydrogen. In another embodiment, R⁵ is halogen.In another embodiment, R⁵ is nitro. In another embodiment, R⁵ iscarbamoyl. In another embodiment, R⁵ is amino. In another embodiment, R⁵is —SO₂R⁸. In another embodiment, R⁵ is —CONR⁹R¹⁰. In anotherembodiment, R⁵ is —(C₁-C₆)alkyl, optionally substituted with one or morehalogen, amino, hydroxyl, or NR⁹R¹⁰. In another embodiment, R⁵ is—(C₁-C₆)alkoxy, optionally substituted with one or more halogen, amino,hydroxyl or NR⁹R¹⁰.

In one embodiment, R⁶ is hydrogen. In another embodiment, R⁶ is halogen.In another embodiment, R⁶ is nitro. In another embodiment, R⁶ iscarbamoyl. In another embodiment, R⁶ is amino. In another embodiment, R⁶is —SO₂R⁸. In another embodiment, R⁶ is —CONR⁹R¹⁰. In anotherembodiment, R⁶ is —(C₁-C₆)alkyl, optionally substituted with one or morehalogen, amino, hydroxyl, or NR⁹R¹⁰. In another embodiment, R⁶ is—(C₁-C₆)alkoxy, optionally substituted with one or more halogen, amino,hydroxyl or NR⁹R¹⁰.

In one embodiment, R⁷ is hydrogen. In another embodiment, R⁷ is halogen.In another embodiment, R⁷ is nitro. In another embodiment, R⁷ iscarbamoyl. In another embodiment, R⁷ is amino. In another embodiment, R⁷is —SO₂R⁸. In another embodiment, R⁷ is —CONR⁹R¹⁰. In anotherembodiment, R⁷ is —(C₁-C₆)alkyl, optionally substituted with one or morehalogen, amino, hydroxyl, or NR⁹R¹⁰. In another embodiment, R⁷ is—(C₁-C₆)alkoxy, optionally substituted with one or more halogen, amino,hydroxyl or NR⁹R¹⁰.

In one embodiment, R⁸ is (C₁-C₆)alkyl, optionally substituted with(C₁-C₆)alkyl or (C₆-C₁₀)aryl. In another embodiment, R⁸ is amino,optionally substituted with (C₁-C₆)alkyl or (C₆-C₁₀)aryl. In anotherembodiment, R⁸ is 6 to 10 membered heterocycle, optionally substitutedwith (C₁-C₆)alkyl or (C₆-C₁₀)aryl.

In one embodiment, R⁹ is hydrogen. In another embodiment, R⁹ is 6 to 10membered aryl. In another embodiment, R⁹ is —COO—(C₁-C₆)alkyl. Inanother embodiment, R⁹ is —(C₀-C₆)alkyl-CHO. In another embodiment, R⁹is —(C₀-C₆)alkyl-COOH. In another embodiment, R⁹ is—(C₀-C₆)alkyl-NR^(9′)R^(10′). In another embodiment, R⁹ is—(C₀-C₆)alkyl-(5 to 10 membered heterocycle). In another embodiment, R⁹is —(C₁-C₆)alkyl-OH. In another embodiment, R⁹ is—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl. In another embodiment, R⁹ is (C₁-C₆)alkyl.In another embodiment, R⁹ is (C₃-C₆)cycloalkyl.

In one embodiment, R¹⁰ is hydrogen. In another embodiment, R¹⁰ is 6 to10 membered aryl. In another embodiment, R¹⁰ is —COO—(C₁-C₆)alkyl. Inanother embodiment, R¹⁰ is —(C₀-C₆)alkyl-CHO. In another embodiment, R¹⁰is —(C₀-C₆)alkyl-COOH. In another embodiment, R¹⁰ is—(C₀-C₆)alkyl-NR^(9′)R^(10′). In another embodiment, R¹⁰ is—(C₀-C₆)alkyl-(5 to 10 membered heterocycle). In another embodiment,R^(1′) is —(C₁-C₆)alkyl-OH. In another embodiment, R¹⁰ is—(C₁-C₆)alkyl-O—(C₁-C₆)alkyl. In another embodiment, R¹⁰ is(C₁-C₆)alkyl. In another embodiment, R¹⁰ is (C₃-C₆)cycloalkyl.

In one embodiment, R⁹ and R¹⁰ together form a 5 to 6 membered ring. Inone embodiment, the ring contains one or more heteroatoms. In oneembodiment, the heteroatoms are selected from the group consisting of N,S and O.

In one embodiment, R^(9′) is hydrogen. In another embodiment, R^(9′) is(C₁-C₆)alkyl.

In one embodiment, R^(10′) is hydrogen. In another embodiment, R^(10′)is (C₁-C₆)alkyl.

In certain embodiments, provided herein are compounds that result fromany combination of R⁵-R¹⁰ and R^(9′)-R^(10′).

In one embodiment, one of R⁵-R⁷ is hydrogen and the remaining two ofR⁵-R⁷ are halogen. In one embodiment, one of R⁵-R⁷ is hydrogen and theremaining two of R⁵—R⁷ are (C₁-C₆)alkoxy. In one embodiment, one ofR⁵-R⁷ is hydrogen and the remaining two of R⁵-R⁷ are (C₁-C₆)alkyl. Inone embodiment, R⁵ is hydrogen, R⁶ is halogen, and R⁷ is (C₁-C₆)alkoxy.

In one embodiment, two of R⁵-R⁷ are hydrogen and the remaining one ofR⁵-R⁷ is halogen. In one embodiment, two of R⁵-R⁷ are hydrogen and theremaining one of R⁵-R⁷ is (C₁-C₆)alkoxy. In one embodiment, two of R⁵-R⁷are hydrogen and the remaining one of R⁵-R⁷ is (C₁-C₆)alkyl.

In one embodiment, specific examples include, but are not limited to:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

In another embodiment, provided herein is a compound of formula (IV):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein:

-   X is N or C;-   Y is CH₂ or C═O;-   R¹¹ and R¹² are each independently hydrogen, —(C₁-C₆)alkyl,    —(C₁-C₆)alkyl-(C₃-C₆)cycloalkyl, —(C₁-C₆)alkoxy, —(C₆-C₁₀)aryl,    —CO(C₁-C₆)alkyl, —CO(C₃-C₆)cycloalkyl, —CO(C₆-C₁₀)aryl,    —COO(C₁-C₆)alkyl, halogen, hydroxyl, oxo, 3 to 10 membered    heterocycle, 6 to 10 membered heteroaryl, —NHCO(C₁-C₆)alkyl,    —(CH₂)_(n)-phenyl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl,    —SO₂(C₆-C₁₀)aryl or —NR¹⁴R¹⁵, wherein the alkyl, aryl or heteroaryl    portion of each of the groups may be optionally substituted with one    or more halogen, hydroxyl or —(C₁-C₆)alkoxy;-   R¹³ is hydrogen or —(C₁-C₆)alkyl;-   R¹⁴ and R¹⁵ are each independently hydrogen or —(C₁-C₆)alkyl; and-   n is 0, 1, 2 or 3.

In one embodiment, X is N. In another embodiment, X is C.

In one embodiment, Y is CH₂. In another embodiment, Y is C═O.

In one embodiment, R¹¹ is hydrogen. In another embodiment, R¹¹ is—(C₁-C₆)alkyl. In another embodiment, R¹¹ is—(C₁-C₆)alkyl-(C₃-C₆)cycloalkyl. In another embodiment, R¹¹ is—(C₁-C₆)alkoxy. In another embodiment, R¹¹ is —(C₆-C₁₀)aryl. In anotherembodiment, R¹¹ is —CO(C₁-C₆)alkyl. In another embodiment, R¹¹ is—CO(C₃-C₆)cycloalkyl. In another embodiment, R¹¹ is —CO(C₆-C₁₀)aryl. Inanother embodiment, R¹¹ is —COO(C₁-C₆)alkyl. In another embodiment, R¹¹is halogen. In another embodiment, R¹¹ is hydroxyl. In anotherembodiment, R¹¹ is oxo. In another embodiment, R¹¹ is 3 to 10 memberedheterocycle. In another embodiment, R¹¹ is 6 to 10 membered heteroaryl.In another embodiment, R¹¹ is —NHCO(C₁-C₆)alkyl. In another embodiment,R¹¹ is —(CH₂)_(n)-phenyl. In another embodiment, R¹¹ is—SO₂(C₁-C₆)alkyl. In another embodiment, R¹¹ is —SO₂(C₃-C₆)cycloalkyl.In another embodiment, R¹¹ is —SO₂(C₆-C₁₀)aryl. In another embodiment,R¹¹ is —NR¹⁴R¹⁵. In another embodiment, is the alkyl, aryl or heteroarylportion of R¹¹ is substituted with one or more halogen, hydroxyl and/or—(C₁-C₆)alkoxy.

In one embodiment, R¹² is hydrogen. In another embodiment, R¹² is—(C₁-C₆)alkyl. In another embodiment, R¹² is—(C₁-C₆)alkyl-(C₃-C₆)cycloalkyl. In another embodiment, R¹² is—(C₁-C₆)alkoxy. In another embodiment, R¹² is —(C₆-C₁₀)aryl. In anotherembodiment, R¹² is —CO(C₁-C₆)alkyl. In another embodiment, R¹² is—CO(C₃-C₆)cycloalkyl. In another embodiment, R¹² is —CO(C₆-C₁₀)aryl. Inanother embodiment, R¹² is —COO(C₁-C₆)alkyl. In another embodiment, R¹²is halogen. In another embodiment, R¹² is hydroxyl. In anotherembodiment, R¹² is oxo. In another embodiment, R¹² is 3 to 10 memberedheterocycle. In another embodiment, R¹² is 6 to 10 membered heteroaryl.In another embodiment, R¹² is —NHCO(C₁-C₆)alkyl. In another embodiment,R¹² is —(CH₂)_(n)-phenyl. In another embodiment, R¹² is—SO₂(C₁-C₆)alkyl. In another embodiment, R¹² is —SO₂(C₃-C₆)cycloalkyl.In another embodiment, R¹² is —SO₂(C₆-C₁₀)aryl. In another embodiment,R¹² is —NR¹⁴R¹⁵. In another embodiment, is the alkyl, aryl or heteroarylportion of R¹² is substituted with one or more halogen, hydroxyl and/or—(C₁-C₆)alkoxy.

In one embodiment, R¹³ is hydrogen. In another embodiment, R¹³ is—(C₁-C₆)alkyl.

In one embodiment, R¹⁴ is hydrogen. In another embodiment, R¹⁴ is—(C₁-C₆)alkyl.

In one embodiment, R¹⁵ is hydrogen. In another embodiment, R¹⁵ is—(C₁-C₆)alkyl.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2. In another embodiment, n is 3.

In one embodiment, provided herein are compounds that result from anycombination of X, Y, R¹¹-R¹⁵ and n as defined above.

In one embodiment, specific examples include, but are not limited to:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

In order embodiment, provided herein are compounds of formula:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salt” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids. Suitable non-toxic acids include inorganic andorganic acids such as, but not limited to, acetic, alginic, anthranilic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,formic, fumaric, furoic, gluconic, glutamic, glucuronic, galacturonic,glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phenylacetic, propionic, phosphoric, salicylic, stearic, succinic,sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Inone embodiment, suitable are hydrochloric, hydrobromic, phosphoric, andsulfuric acids.

As used herein, and unless otherwise specified, the term “solvate” meansa compound that further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Where thesolvent is water, the solvate is a hydrate.

As used herein, and unless otherwise specified, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide thecompound. Examples of prodrugs include, but are not limited to,compounds that comprise biohydrolyzable moieties such as biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogues. Other examples of prodrugs include compounds thatcomprise —NO, —NO₂, —ONO, or —ONO₂ moieties. Prodrugs can typically beprepared using well-known methods, such as those described in Burger'sMedicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E.Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed.,Elselvier, New York 1985).

As used herein, and unless otherwise specified, the terms“biohydrolyzable carbamate,” “biohydrolyzable carbonate,”“biohydrolyzable ureide” and “biohydrolyzable phosphate” mean acarbamate, carbonate, ureide and phosphate, respectively, of a compoundthat either: 1) does not interfere with the biological activity of thecompound but can confer upon that compound advantageous properties invivo, such as uptake, duration of action, or onset of action; or 2) isbiologically inactive but is converted in vivo to the biologicallyactive compound. Examples of biohydrolyzable carbamates include, but arenot limited to, carbamates that include lower alkylamine, substitutedethylenediamine, aminoacid, hydroxyalkylamine, heterocyclic andheteroaromatic amine, and polyether amine moieties.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stereomerically pure andenantiomerically/stereomerically enriched compounds provided herein.

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,greater than about 97% by weight of one stereoisomer of the compound andless than about 3% by weight of the other stereoisomers of the compound,greater than about 98% by weight of one stereoisomer of the compound andless than about 2% by weight of the other stereoisomers of the compoundor greater than about 99% by weight of one stereoisomer of the compoundand less than about 1% by weight of the other stereoisomers of thecompound.

As used herein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, greater than about 70% byweight, or greater than about 80% by weight of one stereoisomer of acompound.

As used herein, and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

As used herein, and unless otherwise indicated, the term “alkyl” refersto a saturated straight chain or branched hydrocarbon having a number ofcarbon atoms as specified herein. In some embodiments, alkyl groups have1 to 15, 1 to 10, 1 to 6, or 1 to 3 carbon atoms. Representativesaturated straight chain alkyls include -methyl, -ethyl, -n-propyl,-n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkylsinclude -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl,2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 2,3-dimethylbutyl, and the like. The term “alkyl” alsoencompasses cycloalkyl.

As used herein, alkenyl refers to a straight chain or branchedhydrocarbon containing one or more double bonds. Exemplary alkenylcarbon chains contain from 2 to 20 carbons, and in certain embodiments,contain 1 to 8 double bonds, and the alkenyl carbon chains of 2 to 16carbons, in certain embodiments, contain 1 to 5 double bonds.

As used herein, alkynyl refers to a straight chain or branchedhydrocarbon containing one or more triple bonds. Alkynyl carbon chainsof from 2 to 20 carbons, in certain embodiments, contain 1 to 8 triplebonds, and the alkynyl carbon chains of 2 to 16 carbons, in certainembodiments, contain 1 to 5 triple bonds. Exemplary alkenyl and alkynylgroups herein include, but are not limited to, ethene, propene, butene,pentene, acetylene and hexyne. As used herein, lower alkyl, loweralkenyl, and lower alkynyl refer to carbon chains having from about 1 orabout 2 carbons up to about 6 carbons.

As used herein, and unless otherwise specified, the term “cycloalkyl”means a specie of alkyl, which is cyclic and contains from 3 to 15, 3 to9, 3 to 6, or 3 to 5 carbon atoms, without alternating or resonatingdouble bonds between carbon atoms. It may contain from 1 to 4 rings.Examples of unsubstituted cycloalkyls include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Acycloalkyl may be substituted with one or more substituents. In someembodiments, a cycloalkyl may be a cycloalkyl fused with aryl orheteroaryl groups.

As used herein, and unless otherwise specified, the term“heterocycloalkyl” means a cycloalkyl in which one or more carbon atomsare replaced by heteroatoms such as, but not limited to, N, S, and O. Insome embodiments, a heterocycloalkyl group contains contains from 2 to14, 2 to 8, 2 to 7, 2 to 5, or 2 to 4 carbon atoms. In some embodiments,a heterocycloalkyl may be a heterocycloalkyl fused with aryl orheteroaryl groups.

As used herein, the term “aryl” means a carbocyclic aromatic ringcontaining from 5 to 14 ring atoms. The ring atoms of a carbocyclic arylgroup are all carbon atoms. Aryl ring structures include compoundshaving one or more ring structures such as mono-, bi-, or tricycliccompounds as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl and the like. Specifically, the aryl groupmay be a mono-, bi-, or tricyclic ring. Representative aryl groupsinclude phenyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyland naphthyl.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system, in certain embodiments, of about 5 to about 15members where one or more, in one embodiment 1 to 3, of the atoms in thering system is a heteroatom, that is, an element other than carbon,including but not limited to, nitrogen, oxygen or sulfur. The heteroarylgroup may be optionally fused to a benzene ring. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, indolinyl,pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl,N-methylpyrrolyl, quinolinyl and isoquinolinyl.

As used herein, “heterocyclyl” refers to a monocyclic or multicyclicnon-aromatic ring system, in one embodiment of 3 to 10 members, inanother embodiment of 4 to 7 members, in a further embodiment of 5 to 6members, where one or more, in certain embodiments, 1 to 3, of the atomsin the ring system is a heteroatom, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen or sulfur. Inembodiments where the heteroatom(s) is(are) nitrogen, the nitrogen isoptionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl,aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, acyl, guanidino, or the nitrogen may be quaternizedto form an ammonium group where the substituents are selected as above.

As used herein, “aralkyl” refers to an alkyl group in which one of thehydrogen atoms of the alkyl is replaced by an aryl group.

As used herein, “heteroaralkyl” refers to an alkyl group in which one ofthe hydrogen atoms of the alkyl is replaced by a heteroaryl group.

As used herein, “alkylaminocarbonyl” refers to C(O)NHR in which R isalkyl, including lower alkyl. As used herein, “dialkylaminocarbonyl”refers to C(O)NR′R in which R′ and R are independently alkyl, includinglower alkyl; “carboxamide” refers to groups of formula —NR′COR in whichR′ and R are independently alkyl, including lower alkyl.

As used herein, “arylaminocarbonyl” refers to —C(O)NHR in which R isaryl, including lower aryl, such as phenyl.

As used herein, “halo”, “halogen” or “halide” refers to F, Cl, Br or I.

Where the number of any given substituent is not specified (e.g.,“haloalkyl”), there may be one or more substituents present. Forexample, “haloalkyl” may include one or more of the same or differenthalogens.

It should be noted that if there is a discrepancy between a depictedstructure and a name given to that structure, the depicted structure isto be accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

4.2 Methods of Treatment, Prevention and Management

Provided herein are methods of treating, preventing, and/or managingvarious diseases or disorders using a compound provided herein, or apharmaceutically acceptable salt, solvate (e.g., hydrate), prodrug,clathrate, or stereoisomer thereof.

Examples of diseases or disorders include, but are not limited to,cancer, disorders associated with angiogenesis, pain including, but notlimited to, Complex Regional Pain Syndrome (“CRPS”), MacularDegeneration (“MD”) and related syndromes, skin diseases, pulmonarydisorders, asbestos-related disorders, parasitic diseases,immunodeficiency disorders, CNS disorders, CNS injury, atherosclerosisand related disorders, dysfunctional sleep and related disorders,hemoglobinopathy and related disorders (e.g., anemia), TNFα relateddisorders, and other various diseases and disorders.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder.

As used herein, unless otherwise specified, the term “preventing” refersto the treatment with or administration of a compound provided herein,with or without other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of cancer and/or otherdisorders described herein. The term “prevention” includes theinhibition or reduction of a symptom of the particular disease. Patientswith familial history of a disease in particular are candidates forpreventive regimens in certain embodiments. In addition, patients whohave a history of recurring symptoms are also potential candidates forthe prevention. In this regard, the term “prevention” may beinterchangeably used with the term “prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. In certain cases, the beneficial effects that asubject derives from a prophylactic or therapeutic agent do not resultin a cure of the disease or disorder.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to inhibit orreduce a symptom of a disease or to prevent recurrence of a disease. Aprophylactically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the inhibition or reduction of asymptom of a disease or recurrence of a disease. The term“prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

Examples of cancer and precancerous conditions include, but are notlimited to, those described in U.S. Pat. Nos. 6,281,230 and 5,635,517 toMuller et al., in various U.S. patent publications to Zeldis, includingpublication nos. 2004/0220144A1, published Nov. 4, 2004 (Treatment ofMyelodysplastic Syndrome); 2004/0029832A1, published Feb. 12, 2004(Treatment of Various Types of Cancer); and 2004/0087546, published May6, 2004 (Treatment of Myeloproliferative Diseases). Examples alsoinclude those described in WO 2004/103274, published Dec. 2, 2004. Allof these references are incorporated herein in their entireties byreference.

Specific examples of cancer include, but are not limited to, cancers ofthe skin, such as melanoma; lymph node; breast; cervix; uterus;gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth;brain; head and neck; throat; testes; kidney; pancreas; bone; spleen;liver; bladder; larynx; nasal passages; and AIDS-related cancers. Thecompounds are also useful for treating cancers of the blood and bonemarrow, such as multiple myeloma and acute and chronic leukemias, forexample, lymphoblastic, myelogenous, lymphocytic, and myelocyticleukemias. The compounds provided herein can be used for treating,preventing or managing either primary or metastatic tumors.

Other specific cancers include, but are not limited to, advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastase, glioblastoma multiforms, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasticleukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma,metastatic melanoma (localized melanoma, including, but not limited to,ocular melanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unresectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another embodiment, the canceris refractory or resistant to chemotherapy or radiation.

In one embodiment, provided herein are methods of treating, preventingor managing various forms of leukemias such as chronic lymphocyticleukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia and acute myeloblastic leukemia, includingleukemias that are relapsed, refractory or resistant, as disclosed inU.S. publication no. 2006/0030594, published Feb. 9, 2006, which isincorporated in its entirety by reference.

The term “leukemia” refers malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another embodiment, provided herein are methods of treating,preventing or managing various types of lymphomas, includingNon-Hodgkin's lymphoma (NHL). The term “lymphoma” refers a heterogenousgroup of neoplasms arising in the reticuloendothelial and lymphaticsystems. “NHL” refers to malignant monoclonal proliferation of lymphoidcells in sites of the immune system, including lymph nodes, bone marrow,spleen, liver and gastrointestinal tract. Examples of NHL include, butare not limited to, mantle cell lymphoma (MCL), lymphocytic lymphoma ofintermediate differentiation, intermediate lymphocytic lymphoma (ILL),diffuse poorly differentiated lymphocytic lymphoma (PDL), centrocyticlymphoma, diffuse small-cleaved cell lymphoma (DSCCL), follicularlymphoma, and any type of the mantle cell lymphomas that can be seenunder the microscope (nodular, diffuse, blastic and mantle zonelymphoma).

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle). Specific examples of thediseases and disorders associated with, or characterized by, undesiredangiogenesis include, but are not limited to, arthritis, endometriosis,Crohn's disease, heart failure, advanced heart failure, renalimpairment, endotoxemia, toxic shock syndrome, osteoarthritis,retrovirus replication, wasting, meningitis, silica-induced fibrosis,asbestos-induced fibrosis, veterinary disorder, malignancy-associatedhypercalcemia, stroke, circulatory shock, periodontitis, gingivitis,macrocytic anemia, refractory anemia, and 5q-deletion syndrome.

Examples of pain include, but are not limited to those described in U.S.patent publication no. 2005/0203142, published Sep. 15, 2005, which isincorporated herein by reference. Specific types of pain include, butare not limited to, nociceptive pain, neuropathic pain, mixed pain ofnociceptive and neuropathic pain, visceral pain, migraine, headache andpost-operative pain.

Examples of nociceptive pain include, but are not limited to, painassociated with chemical or thermal burns, cuts of the skin, contusionsof the skin, osteoarthritis, rheumatoid arthritis, tendonitis, andmyofascial pain.

Examples of neuropathic pain include, but are not limited to, CRPS type1, CRPS type II, reflex sympathetic dystrophy (RSD), reflexneurovascular dystrophy, reflex dystrophy, sympathetically maintainedpain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy,shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia,post herpetic neuralgia, cancer related pain, phantom limb pain,fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, centralpost-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain,luetic neuropathy, and other painful neuropathic conditions such asthose induced by drugs such as vincristine and velcade.

As used herein, the terms “complex regional pain syndrome,” “CRPS” and“CRPS and related syndromes” mean a chronic pain disorder characterizedby one or more of the following: pain, whether spontaneous or evoked,including allodynia (painful response to a stimulus that is not usuallypainful) and hyperalgesia (exaggerated response to a stimulus that isusually only mildly painful); pain that is disproportionate to theinciting event (e.g., years of severe pain after an ankle sprain);regional pain that is not limited to a single peripheral nervedistribution; and autonomic dysregulation (e.g., edema, alteration inblood flow and hyperhidrosis) associated with trophic skin changes (hairand nail growth abnormalities and cutaneous ulceration).

Examples of MD and related syndromes include, but are not limited to,those described in U.S. patent publication no. 2004/0091455, publishedMay 13, 2004, which is incorporated herein by reference. Specificexamples include, but are not limited to, atrophic (dry) MD, exudative(wet) MD, age-related maculopathy (ARM), choroidal neovascularisation(CNVM), retinal pigment epithelium detachment (PED), and atrophy ofretinal pigment epithelium (RPE).

Examples of skin diseases include, but are not limited to, thosedescribed in U.S. publication no. 2005/0214328A1, published Sep. 29,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, keratoses and related symptoms, skindiseases or disorders characterized with overgrowths of the epidermis,acne, and wrinkles.

As used herein, the term “keratosis” refers to any lesion on theepidermis marked by the presence of circumscribed overgrowths of thehorny layer, including but not limited to actinic keratosis, seborrheickeratosis, keratoacanthoma, keratosis follicularis (Darier disease),inverted follicular keratosis, palmoplantar keratoderma (PPK, keratosispalmaris et plantaris), keratosis pilaris, and stucco keratosis. Theterm “actinic keratosis” also refers to senile keratosis, keratosissenilis, verruca senilis, plana senilis, solar keratosis, keratoderma orkeratoma. The term “seborrheic keratosis” also refers to seborrheicwart, senile wart, or basal cell papilloma. Keratosis is characterizedby one or more of the following symptoms: rough appearing, scaly,erythematous papules, plaques, spicules or nodules on exposed surfaces(e.g., face, hands, ears, neck, legs and thorax), excrescences ofkeratin referred to as cutaneous horns, hyperkeratosis, telangiectasias,elastosis, pigmented lentigines, acanthosis, parakeratosis,dyskeratoses, papillomatosis, hyperpigmentation of the basal cells,cellular atypia, mitotic figures, abnormal cell-cell adhesion, denseinflammatory infiltrates and small prevalence of squamous cellcarcinomas.

Examples of skin diseases or disorders characterized with overgrowths ofthe epidermis include, but are not limited to, any conditions, diseasesor disorders marked by the presence of overgrowths of the epidermis,including but not limited to, infections associated with papillomavirus, arsenical keratoses, sign of Leser-Trélat, warty dyskeratoma(WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV),ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneousmelanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,confluent and reticulated papillomatosis (CRP), acrochordons, cutaneoushorn, cowden disease (multiple hamartoma syndrome), dermatosis papulosanigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris,molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

Examples of pulmonary disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0239842A1, published Oct. 27,2005, which is incorporated herein by reference. Specific examplesinclude pulmonary hypertension and related disorders. Examples ofpulmonary hypertension and related disorders include, but are notlimited to: primary pulmonary hypertension (PPH); secondary pulmonaryhypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonaryhypertension; pulmonary arterial hypertension (PAH); pulmonary arteryhypertension; idiopathic pulmonary hypertension; thrombotic pulmonaryarteriopathy (TPA); plexogenic pulmonary arteriopathy; functionalclasses I to IV pulmonary hypertension; and pulmonary hypertensionassociated with, related to, or secondary to, left ventriculardysfunction, mitral valvular disease, constrictive pericarditis, aorticstenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonaryvenous drainage, pulmonary venoocclusive disease, collagen vasulardisease, congenital heart disease, HIV virus infection, drugs and toxinssuch as fenfluramines, congenital heart disease, pulmonary venoushypertension, chronic obstructive pulmonary disease, interstitial lungdisease, sleep-disordered breathing, alveolar hypoventilation disorder,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorder, chronic thromboemboli, connective tissue disease, lupusincluding systemic and cutaneous lupus, schistosomiasis, sarcoidosis orpulmonary capillary hemangiomatosis.

Examples of asbestos-related disorders include, but not limited to,those described in U.S. publication no. 2005/0100529, published May 12,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, mesothelioma, asbestosis, malignantpleural effusion, benign exudative effusion, pleural plaques, pleuralcalcification, diffuse pleural thickening, rounded atelectasis, fibroticmasses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, thosedescribed in U.S. publication no. 2006/0154880, published Jul. 13, 2006,which is incorporated herein by reference. Parasitic diseases includediseases and disorders caused by human intracellular parasites such as,but not limited to, P. falcifarium, P. ovale, P. vivax, P. malariae, L.donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. mexicana,L. braziliensis, T. Gondii, B. microti, B. divergens, B. coli, C.parvum, C. cayetanensis, E. histolytica, I. belli, S. mansonii, S.haematobium, Trypanosoma ssp., Toxoplasma ssp., and O. volvulus. Otherdiseases and disorders caused by non-human intracellular parasites suchas, but not limited to, Babesia bovis, Babesia canis, Banesia Gibsoni,Besnoitia darlingi, Cytauxzoonfelis, Eimeria ssp., Hammondia ssp., andTheileria ssp., are also encompassed. Specific examples include, but arenot limited to, malaria, babesiosis, trypanosomiasis, leishmaniasis,toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis,cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,filariasis, schistosomiasis, and dermatitis caused by animalschistosomes.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. application Ser. No. 11/289,723, filed Nov. 30,2005. Specific examples include, but not limited to, adenosine deaminasedeficiency, antibody deficiency with normal or elevated Igs,ataxia-telangiectasia, bare lymphocyte syndrome, common variableimmunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions, IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective lgG subclass deficiency,transient hypogammaglobulinemia of infancy, Wistcott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0143344, published Jun. 30, 2005,which is incorporated herein by reference. Specific examples include,but are not limited to, include, but are not limited to, AmyotrophicLateral Sclerosis, Alzheimer Disease, Parkinson Disease, Huntington'sDisease, Multiple Sclerosis other neuroimmunological disorders such asTourette Syndrome, delerium, or disturbances in consciousness that occurover a short period of time, and amnestic disorder, or discreet memoryimpairments that occur in the absence of other central nervous systemimpairments.

Examples of CNS injuries and related syndromes include, but are notlimited to, those described in U.S. publication no. 2006/0122228,published Jun. 8, 2006, which is incorporated herein by reference.Specific examples include, but are not limited to, CNS injury/damage andrelated syndromes, include, but are not limited to, primary braininjury, secondary brain injury, traumatic brain injury, focal braininjury, diffuse axonal injury, head injury, concussion, post-concussionsyndrome, cerebral contusion and laceration, subdural hematoma,epidermal hematoma, post-traumatic epilepsy, chronic vegetative state,complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI,central cord syndrome, Brown-Sequard syndrome, anterior cord syndrome,conus medullaris syndrome, cauda equina syndrome, neurogenic shock,spinal shock, altered level of consciousness, headache, nausea, emesis,memory loss, dizziness, diplopia, blurred vision, emotional lability,sleep disturbances, irritability, inability to concentrate, nervousness,behavioral impairment, cognitive deficit, and seizure.

Other disease or disorders include, but not limited to, viral, genetic,allergic, and autoimmune diseases. Specific examples include, but notlimited to, HIV, hepatitis, adult respiratory distress syndrome, boneresorption diseases, chronic pulmonary inflammatory diseases,dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock,hemodynamic shock, sepsis syndrome, post. ischemic reperfusion injury,meningitis, psoriasis, fibrotic disease, cachexia, graft versus hostdisease, graft rejection, auto-immune disease, rheumatoid spondylitis,Crohn's disease, ulcerative colitis, inflammatory-bowel disease,multiple sclerosis, systemic lupus erythematosus, ENL in leprosy,radiation damage, cancer, asthma, or hyperoxic alveolar injury.

Examples of atherosclerosis and related conditions include, but are notlimited to, those disclosed in U.S. publication no. 2002/0054899,published May 9, 2002, which is incorporated herein by reference.Specific examples include, but are not limited to, all forms ofconditions involving atherosclerosis, including restenosis aftervascular intervention such as angioplasty, stenting, atherectomy andgrafting. All forms of vascular intervention are contemplated herein,including diseases of the cardiovascular and renal system, such as, butnot limited to, renal angioplasty, percutaneous coronary intervention(PCI), percutaneous transluminal coronary angioplasty (PTCA), carotidpercutaneous transluminal angioplasty (PTA), coronary by-pass grafting,angioplasty with stent implantation, peripheral percutaneoustransluminal intervention of the iliac, femoral or popliteal arteries,and surgical intervention using impregnated artificial grafts. Thefollowing chart provides a listing of the major systemic arteries thatmay be in need of treatment, all of which are contemplated herein:

TABLE 1 Artery Body Areas Supplied Axillary Shoulder and axilla BrachialUpper arm Brachiocephalic Head, neck, and arm Celiac Divides into leftgastric, splenic, and hepatic arteries Common carotid Neck Common iliacDivides into external and internal iliac arteries Coronary Heart Deepfemoral Thigh Digital Fingers Dorsalis pedis Foot External carotid Neckand external head regions External iliac Femoral artery Femoral ThighGastric Stomach Hepatic Liver, gallbladder, pancreas, and duodenumInferior mesenteric Descending colon, rectum, and pelvic wall Internalcarotid Neck and internal head regions Internal iliac Rectum, urinarybladder, external genitalia, buttocks Left gastric muscles, uterus andvagina Middle sacral Esophagus and stomach Ovarian Sacrum Palmar archOvaries Peroneal Hand Popliteal Calf Posterior tibial Knee PulmonaryCalf Radial Lungs Renal Forearm Splenic Kidney Subclavian Stomach,pancreas, and spleen Superior mesenteric Shoulder Testicular Pancreas,small intestine, ascending and transverse colon Ulnar Testes Forearm

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. publication no. 2005/0222209A1,published Oct. 6, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, snoring, sleep apnea,insomnia, narcolepsy, restless leg syndrome, sleep terrors, sleepwalking sleep eating, and dysfunctional sleep associated with chronicneurological or inflammatory conditions. Chronic neurological orinflammatory conditions, include, but are not limited to, ComplexRegional Pain Syndrome, chronic low back pain, musculoskeletal pain,arthritis, radiculopathy, pain associated with cancer, fibromyalgia,chronic fatigue syndrome, visceral pain, bladder pain, chronicpancreatitis, neuropathies (diabetic, post-herpetic, traumatic orinflammatory), and neurodegenerative disorders such as Parkinson'sDisease, Alzheimer's Disease, amyotrophic lateral sclerosis, multiplesclerosis, Huntington's Disease, bradykinesia; muscle rigidity;parkinsonian tremor; parkinsonian gait; motion freezing; depression;defective long-term memory, Rubinstein-Taybi syndrome (RTS); dementia;postural instability; hypokinetic disorders; synuclein disorders;multiple system atrophies; striatonigral degeneration;olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron diseasewith parkinsonian features; Lewy body dementia; Tau pathology disorders;progressive supranuclear palsy; corticobasal degeneration;frontotemporal dementia; amyloid pathology disorders; mild cognitiveimpairment; Alzheimer disease with parkinsonism; Wilson disease;Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3spinocerebellar ataxia; X-linked dystonia parkinsonism; prion disease;hyperkinetic disorders; chorea; ballismus; dystonia tremors; AmyotrophicLateral Sclerosis (ALS); CNS trauma and myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. publication no. 2005/0143420A1,published Jun. 30, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, hemoglobinopathy,sickle cell anemia, and any other disorders related to thedifferentiation of CD34+ cells.

Examples of TNFα related disorders include, but are not limited to,those described in WO 98/03502 and WO 98/54170, both of which areincorporated herein in their entireties by reference. Specific examplesinclude, but are not limited to: endotoxemia or toxic shock syndrome;cachexia; adult respiratory distress syndrome; bone resorption diseasessuch as arthritis; hypercalcemia; Graft versus Host Reaction; cerebralmalaria; inflammation; tumor growth; chronic pulmonary inflammatorydiseases; reperfusion injury; myocardial infarction; stroke; circulatoryshock; rheumatoid arthritis; Crohn's disease; HIV infection and AIDS;other disorders such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, psoriatic arthritis and other arthritic conditions,septic shock, sepsis, endotoxic shock, graft versus host disease,wasting, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythromatosis, ENL in leprosy, HIV, AIDS, andopportunistic infections in AIDS; disorders such as septic shock,sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, postischemic reperfusion injury, malaria, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic disease,cachexia, graft rejection, oncogenic or cancerous conditions, asthma,autoimmune disease, radiation damages, and hyperoxic alveolar injury;viral infections, such as those caused by the herpes viruses; viralconjunctivitis; or atopic dermatitis.

In other embodiments, the use of compounds provided herein in variousimmunological applications, i.e., use of compounds provided herein incombination with a vaccination, for example, as vaccine adjuvant.Although any methods and manners of use of compounds provided herein incombination with a vaccine are contemplated herein, a non-limitingexample of such uses is the use of compounds provided herein as vaccineadjuvants, according to the administration regimens disclosed in U.S.Provisional Application No. 60/712,823, filed Sep. 1, 2005, which isincorporated herein in its entirety by reference. These embodiments alsorelate to the uses of compounds provided herein in combination withvaccines to treat or prevent cancer or infectious diseases, and othervarious uses of compounds provided herein, such as, but not limited to,reduction or desensitization of allergic reactions.

Doses of a compound provided herein, or a pharmaceutically acceptablesalt, solvate, clathrate, stereoisomer or prodrug thereof, varydepending on factors such as: specific indication to be treated,prevented, or managed; age and condition of a patient; and amount ofsecond active agent used, if any. Generally, a compound provided herein,or a pharmaceutically acceptable salt, solvate, clathrate, stereoisomeror prodrug thereof, may be used in an amount of from about 0.1 mg toabout 500 mg per day, and can be adjusted in a conventional fashion(e.g., the same amount administered each day of the treatment,prevention or management period), in cycles (e.g., one week on, one weekoff), or in an amount that increases or decreases over the course oftreatment, prevention, or management. In other embodiments, the dose canbe from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg,from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, fromabout 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1mg to about 20 mg.

4.3 Second Active Agents

A compound provided herein, or a pharmaceutically acceptable salt,solvate, prodrug, clathrate, or stereoisomer thereof, can be combinedwith other pharmacologically active compounds (“second active agents”)in methods and compositions provided herein. Certain combinations maywork synergistically in the treatment of particular types diseases ordisorders, and conditions and symptoms associated with such diseases ordisorders. A compound provided herein, or a pharmaceutically acceptablesalt, solvate, clathrate, stereoisomer or prodrug thereof, can also workto alleviate adverse effects associated with certain second activeagents, and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40); histonedeacetlyase inhibitors (such as, for example, SAHA and LAQ 824);heat-shock protein-90 inhibitors (such as, for example, 17-AAG);insulin-like growth factor-1 receptor kinase inhibitors; vascularendothelial growth factor receptor kinase inhibitors (such as, forexample, PTK787); insulin growth factor receptor inhibitors;lysophosphatidic acid acyltransrerase inhibitors; IkB kinase inhibitors;p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib anderlotinib HCL); HER-2 antibodies (such as, for example, trastuzumab(Herceptin®) and pertuzumab (Omnitarg™)); VEGFR antibodies (such as, forexample, bevacizumab (Avastin™)); VEGFR inhibitors (such as, forexample, flk-1 specific kinase inhibitors, SU5416 and ptk787/zk222584);PI3K inhibitors (such as, for example, wortmannin); C-Met inhibitors(such as, for example, PHA-665752); monoclonal antibodies (such as, forexample, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab(Panorex®) and G250); and anti-TNF-α antibodies. Examples of smallmolecule active agents include, but are not limited to, anticanceragents and antibiotics (e.g., clarithromycin).

Specific second active compounds that can be combined with compoundsprovided herein vary depending on the specific indication to be treated,prevented or managed.

For instance, for the treatment, prevention or management of cancer,second active agents include, but are not limited to: semaxanib;cyclosporin; etanercept; doxycycline; bortezomib; lapatinib (Tykerb®);acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin;aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; celecoxib; chlorambucil;cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+ estrogen+ progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lyticpeptides; maitansine; mannostatin A; marimastat; masoprocol; maspin;matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril;merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, humanchorionic gonadotrophin; monophosphoryl lipid A+ myobacterium cell wallsk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterialcell wall extract; myriaporone; N-acetyldinaline; N-substitutedbenzamides; nafarelin; nagrestip; naloxone+ pentazocine; napavin;naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;nitrullyn; oblimersen (Genasense®); 06-benzylguanine; octreotide;okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillylalcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetinA; placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginoneBI; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stipiamide; stromelysininhibitors; sulfinosine; superactive vasoactive intestinal peptideantagonist; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in mutiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

In another embodiment, examples of specific second agents according tothe indications to be treated, prevented, or managed can be found in thefollowing references, all of which are incorporated herein in theirentireties: U.S. Pat. Nos. 6,281,230 and 5,635,517; U.S. publicationnos. 2004/0220144, 2004/0190609, 2004/0087546, 2005/0203142,2004/0091455, 2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880,2006/0122228, and 2005/0143344; and U.S. provisional application No.60/631,870.

Examples of second active agents that may be used for the treatment,prevention and/or management of pain include, but are not limited to,conventional therapeutics used to treat or prevent pain such asantidepressants, anticonvulsants, antihypertensives, anxiolytics,calcium channel blockers, muscle relaxants, non-narcotic analgesics,opioid analgesics, anti-inflammatories, cox-2 inhibitors,immunomodulatory agents, alpha-adrenergic receptor agonists orantagonists, immunosuppressive agents, corticosteroids, hyperbaricoxygen, ketamine, other anesthetic agents, NMDA antagonists, and othertherapeutics found, for example, in the Physician's Desk Reference 2003.Specific examples include, but are not limited to, salicylic acidacetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin(Neurontin®), phenytoin (Dilantin®), carbamazepine (Tegretol®),oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate,hydromorphone, prednisone, griseofulvin, penthonium, alendronate,dyphenhydramide, guanethidine, ketorolac (Acular®), thyrocalcitonin,dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin,reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine,acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®),imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®),fluoxetine (Prozac®), sertraline (Zoloft®), naproxen, nefazodone(Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®), bupropion(Wellbutrin®), mexiletine, nifedipine, propranolol, tramadol,lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan,benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Examples of second active agents that may be used for the treatment,prevention and/or management of macular degeneration and relatedsyndromes include, but are not limited to, a steroid, a lightsensitizer, an integrin, an antioxidant, an interferon, a xanthinederivative, a growth hormone, a neutrotrophic factor, a regulator ofneovascularization, an anti-VEGF antibody, a prostaglandin, anantibiotic, a phytoestrogen, an anti-inflammatory compound or anantiangiogenesis compound, or a combination thereof. Specific examplesinclude, but are not limited to, verteporfin, purlytin, an angiostaticsteroid, rhuFab, interferon-2α, pentoxifylline, tin etiopurpurin,motexafin, lucentis, lutetium, 9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione, latanoprost(see U.S. Pat. No. 6,225,348), tetracycline and its derivatives,rifamycin and its derivatives, macrolides, metronidazole (U.S. Pat. Nos.6,218,369 and 6,015,803), genistein, genistin, 6′-O-Mal genistin,6′-O-Ac genistin, daidzein, daidzin, 6′-O-Mal daidzin, 6′-O—Ac daidzin,glycitein, glycitin, 6′-O-Mal glycitin, biochanin A, formononetin (U.S.Pat. No. 6,001,368), triamcinolone acetomide, dexamethasone (U.S. Pat.No. 5,770,589), thalidomide, glutathione (U.S. Pat. No. 5,632,984),basic fibroblast growth factor (bFGF), transforming growth factor b(TGF-b), brain-derived neurotrophic factor (BDNF), plasminogen activatorfactor type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (EliLilly), Miravant, and RETISERT implant (Bausch & Lomb). All of thereferences cited herein are incorporated in their entireties byreference.

Examples of second active agents that may be used for the treatment,prevention and/or management of skin diseases include, but are notlimited to, keratolytics, retinoids, α-hydroxy acids, antibiotics,collagen, botulinum toxin, interferon, steroids, and immunomodulatoryagents. Specific examples include, but are not limited to,5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lacticacid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics,collagen, botulinum toxin, interferon, corticosteroid, transretinoicacid and collagens such as human placental collagen, animal placentalcollagen, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm,Zyplast, Resoplast, and Isolagen.

Examples of second active agents that may be used for the treatment,prevention and/or management of pulmonary hypertension and relateddisorders include, but are not limited to, anticoagulants, diuretics,cardiac glycosides, calcium channel blockers, vasodilators, prostacyclinanalogues, endothelin antagonists, phosphodiesterase inhibitors (e.g.,PDE V inhibitors), endopeptidase inhibitors, lipid lowering agents,thromboxane inhibitors, and other therapeutics known to reduce pulmonaryartery pressure. Specific examples include, but are not limited to,warfarin (Coumadin®), a diuretic, a cardiac glycoside, digoxin-oxygen,diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g.,prostaglandin 12 (PGI2), epoprostenol (EPO, Floran®), treprostinil(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine,epoprostenol (Floran®), treprostinil (Remodulin®), prostacyclin,tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat (Vanlev®),irbesartan (Avapro®), pravastatin (Pravachol®), digoxin, L-arginine,iloprost, betaprost, and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment,prevention and/or management of asbestos-related disorders include, butare not limited to, anthracycline, platinum, alkylating agent,oblimersen (Genasense®), cisplatinum, cyclophosphamide, temodar,carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine,carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid,palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenictrioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir,adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa,tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment,prevention and/or management of parasitic diseases include, but are notlimited to, chloroquine, quinine, quinidine, pyrimethamine,sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine,primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin,suramin, pentamidine, melarsoprol, nifurtimox, benznidazole,amphotericin B, pentavalent antimony compounds (e.g., sodiumstiboglucuronate), interfereon gamma, itraconazole, a combination ofdead promastigotes and BCG, leucovorin, corticosteroids, sulfonamide,spiramycin, IgG (serology), trimethoprim, and sulfamethoxazole.

Examples of second active agents that may be used for the treatment,prevention and/or management of immunodeficiency disorders include, butare not limited to: antibiotics (therapeutic or prophylactic) such as,but not limited to, ampicillin, tetracycline, penicillin,cephalosporins, streptomycin, kanamycin, and erythromycin; antiviralssuch as, but not limited to, amantadine, rimantadine, acyclovir, andribavirin; immunoglobulin; plasma; immunologic enhancing drugs such as,but not limited to, levami sole and isoprinosine; biologics such as, butnot limited to, gammaglobulin, transfer factor, interleukins, andinterferons; hormones such as, but not limited to, thymic; and otherimmunologic agents such as, but not limited to, B cell stimulators(e.g., BAFF/BIyS), cytokines (e.g., IL-2, IL-4, and IL-5), growthfactors (e.g., TGF-α), antibodies (e.g., anti-CD40 and IgM),oligonucleotides containing unmethylated CpG motifs, and vaccines (e.g.,viral and tumor peptide vaccines).

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS disorders include, but are notlimited to: opioids; a dopamine agonist or antagonist, such as, but notlimited to, Levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine,tetrabenazine, benzotropine, pargyline, fenodolpam mesylate,cabergoline, pramipexole dihydrochloride, ropinorole, amantadinehydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate,Sinemet CR, and Symmetrel; a MAO inhibitor, such as, but not limited to,iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT inhibitor,such as, but not limited to, tolcapone and entacapone; a cholinesteraseinhibitor, such as, but not limited to, physostigmine saliclate,physostigmine sulfate, physostigmine bromide, meostigmine bromide,neostigmine methylsulfate, ambenonim chloride, edrophonium chloride,tacrine, pralidoxime chloride, obidoxime chloride, trimedoxime bromide,diacetyl monoxim, endrophonium, pyridostigmine, and demecarium; ananti-inflammatory agent, such as, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone or betamethasone and other glucocorticoids; and anantiemetic agent, such as, but not limited to, metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS injuries and related syndromesinclude, but are not limited to, immunomodulatory agents,immunosuppressive agents, antihypertensives, anticonvulsants,fibrinolytic agents, antiplatelet agents, antipsychotics,antidepressants, benzodiazepines, buspirone, amantadine, and other knownor conventional agents used in patients with CNS injury/damage andrelated syndromes. Specific examples include, but are not limited to:steroids (e.g., glucocorticoids, such as, but not limited to,methylprednisolone, dexamethasone and betamethasone); ananti-inflammatory agent, including, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, RHo-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone; a cAMP analog including, but not limited to, db-cAMP; anagent comprising a methylphenidate drug, which comprisesI-threo-methylphenidate, d-threo-methylphenidate,dl-threo-methylphenidate, l-erythro-methylphenidate,d-erythro-methylphenidate, dl-erythro-methylphenidate, and a mixturethereof; and a diuretic agent such as, but not limited to, mannitol,furosemide, glycerol, and urea.

Examples of second active agent that may be used for the treatment,prevention and/or management of dysfunctional sleep and relatedsyndromes include, but are not limited to, a tricyclic antidepressantagent, a selective serotonin reuptake inhibitor, an antiepileptic agent(gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam,topiramate), an antiaryhthmic agent, a sodium channel blocking agent, aselective inflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,fenodolpam mesylate, cabergoline, pramipexole dihydrochloride,ropinorole, amantadine hydrochloride, selegiline hydrochloride,carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazid,clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine saliclate, physostigmine sulfate, physostigmine bromide,meostigmine bromide, neostigmine methylsulfate, ambenonim chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxim, endrophonium, pyridostigmine,demecarium, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betamethasone and other glucocorticoids, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of hemoglobinopathy and related disordersinclude, but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrates or butyrate derivatives; nitrousoxide; hydroxy urea; HEMOXIN™ (NIPRISAN™; see U.S. Pat. No. 5,800,819);Gardos channel antagonists such as clotrimazole and triaryl methanederivatives; Deferoxamine; protein C; and transfusions of blood, or of ablood substitute such as Hemospan™ or Hemospan™ PS (Sangart).

Administration of a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, clathrate, stereoisomer or prodrug thereof,and the second active agents to a patient can occur simultaneously orsequentially by the same or different routes of administration. Thesuitability of a particular route of administration employed for aparticular active agent will depend on the active agent itself (e.g.,whether it can be administered orally without decomposing prior toentering the blood stream) and the disease being treated. One ofadministration for compounds provided herein is oral. Routes ofadministration for the second active agents or ingredients are known tothose of ordinary skill in the art. See, e.g., Physicians' DeskReference (60^(th) ed., 2006).

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount(s) of compounds provided herein and any optional additionalactive agents concurrently administered to the patient.

As discussed elsewhere herein, also encompassed is a method of reducing,treating and/or preventing adverse or undesired effects associated withconventional therapy including, but not limited to, surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapyand immunotherapy. Compounds provided herein and other activeingredients can be administered to a patient prior to, during, or afterthe occurrence of the adverse effect associated with conventionaltherapy.

4.4 Cycling Therapy

In certain embodiments, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in one embodiment, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another embodiment encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another embodiment, a compound providedherein is administered for a greater number of cycles than wouldtypically cause dose-limiting toxicity in a patient to whom a secondactive ingredient is not also being administered.

In one embodiment, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 mg toabout 500 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 300 mg, from about0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg toabout 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about30 mg, or from about 1 mg to about 20 mg, followed by a rest.

In one embodiment, a compound provided herein and a second activeingredient are administered orally, with administration of the compoundprovided herein occurring 30 to 60 minutes prior to the second activeingredient, during a cycle of four to six weeks. In another embodiment,the combination of a compound provided herein and a second activeingredient is administered by intravenous infusion over about 90 minutesevery cycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

4.5 Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt, solvate, stereoisomer, clathrate, orprodrug thereof. Pharmaceutical compositions and dosage forms canfurther comprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are disclosed in Section 4.3,above.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 20^(th) ed., Mack Publishing,Easton Pa. (2000).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or di-saccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are anhydrous if substantial contact withmoisture and/or humidity during manufacturing, packaging, and/or storageis expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg. Inother embodiments, dosage forms comprise a compound provided herein inan amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50,100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise the second active ingredientin an amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound provided herein, and any optionaladditional active agents concurrently administered to the patient.

4.5.1 Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 20th ed., Mack Publishing, Easton Pa. (2000).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or nonaqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. In oneembodiment, pharmaceutical compositions comprise from about 0.5 to about15 weight percent of disintegrant, or from about 1 to about 5 weightpercent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W. R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, anhydrous lactose, microcrystalline cellulose,polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, andgelatin.

4.5.2 Controlled Release Dosage Forms

Active ingredients such as the compounds provided herein can beadministered by controlled release means or by delivery devices that arewell known to those of ordinary skill in the art. Examples include, butare not limited to, those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; and U.S. Pat. Nos. 4,008,719;5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476;5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356;5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943;6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961;6,589,548; 6,613,358; 6,699,500 each of which is incorporated herein byreference. Such dosage forms can be used to provide slow or controlledrelease of one or more active ingredients using, for example,hydropropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled releaseformulations known to those of ordinary skill in the art, includingthose described herein, can be readily selected for use with the activeingredients provided herein. Thus, the compositions provided encompasssingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non controlledcounterparts. Ideally, the use of an optimally designed controlledrelease preparation in medical treatment is characterized by a minimumof drug substance being employed to cure or control the condition in aminimum amount of time. Advantages of controlled release formulationsinclude extended activity of the drug, reduced dosage frequency, andincreased subject compliance. In addition, controlled releaseformulations can be used to affect the time of onset of action or othercharacteristics, such as blood levels of the drug, and can thus affectthe occurrence of side (e.g., adverse) effects.

Most controlled release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the drug may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In one embodiment, a pump may be used(see, Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al.,Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)).In another embodiment, polymeric materials can be used. In yet anotherembodiment, a controlled release system can be placed in a subject at anappropriate site determined by a practitioner of skill, i.e., thusrequiring only a fraction of the systemic dose (see, e.g., Goodson,Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)).Other controlled release systems are discussed in the review by Langer(Science 249:1527-1533 (1990)). The active ingredient can be dispersedin a solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient in such parenteral compositions is highly dependent onthe specific nature thereof, as well as the needs of the subject.

4.5.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

4.5.4 Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences,16^(th), 18^(th) and 20^(th) eds., Mack Publishing, Easton Pa. (1980,1990 and 2000); and Introduction to Pharmaceutical Dosage Forms, 4thed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16^(th), 18^(th) and 20^(th) eds., MackPublishing, Easton Pa. (1980, 1990 and 2000).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

4.6 Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise additional active ingredients such asoblimersen (Genasense®), melphalan, G-CSF, GM-CSF, EPO, topotecan,dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor, pentoxifylline,ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine,isotretinoin, 13 cis-retinoic acid, or a pharmacologically active mutantor derivative thereof, or a combination thereof. Examples of theadditional active ingredients include, but are not limited to, thosedisclosed herein (see, e.g., section 4.3).

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

5. EXAMPLES

Certain embodiments of the claimed subject matter are illustrated by thefollowing non-limiting examples.

5.1 4-CARBAMOYL-4-(4-HYDROXY-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-BUTYRICACID METHYL ESTER

5.1.1 3-Hydroxy-2-methyl-benzoic acid methyl ester

3-Hydroxy-2-methylbenzoic acid (105 g, 690 mmol) was added to MeOH (800mL) in a 2 L three neck round bottom flask equipped with condenser,thermometer and stirring bar followed by the addition of MeOH (250 ml).H₂SO₄ (10 mL, 180 mmol) was added to above solution. The reactionmixture was stirred at 62° C. for 17 hours. The solvent was removed invacuo. The residue (200 mL) was added to water (600 mL) slowly at roomtemperature and a white solid was formed. The suspension was stirred inan ice bath for 30 minutes and filtered. The solid was washed with water(5×250 mL) and dried to give 3-hydroxy-2-methyl-benzoic acid methylester as a white solid (100 g, 87% yield). The compound was used in thenext step without further purification: LCMS MH=167; 1H NMR (DMSO-d₆) δ2.28 (s, 3H, CH₃), 3.80 (s, 3H, CH₃), 6.96-7.03 (m, 1H, Ar), 7.09 (t,J=7.8 Hz, 1H, Ar), 7.14-7.24 (m, 1H, Ar), 9.71 (s, 1H, OH).

5.1.2 3-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-benzoic acid methylester

To a 1 L three neck RB flask equipped with stirring bar and thermometer,were added DMF (300 mL), methyl 3-hydroxy-2-methylbenzoate (90 g, 542mmol) and imidazole (92 g, 1,354 mmol). TBDMS-Cl (90 g, 596 mmol) wasadded to the above solution in portions to control the internal tempbetween 15-19° C. over 20 minutes, and after addition, the internal tempdropped below 1° C. The ice bath was removed and the reaction mixturewas stirred at room temperature for 16 hours. The reaction mixture wasadded to ice water (500 mL), and the resulting solution was divided intotwo portions (700 mL×2). Each portion was extracted with EtOAc (700 mL).Each organic layer was washed with cold water (350 mL) and brine (350mL). Organic layers were combined and dried by MgSO₄. The combinedorganic layer was concentrated to give3-(tert-butyl-dimethyl-silanyloxy)-2-methyl-benzoic acid methyl ester asa light brown oil (160 g, 100% crude yield). The compound was used inthe next step without further purification: LCMS MH=281; ¹H NMR(DMSO-d₆) δ −0.21 (s, 6H, CH₃, CH₃), 0.73-0.84 (m, 9H, CH₃, CH₃, CH₃),2.10 (s, 3H, CH₃), 3.60 (s, 3H, CH₃), 6.82 (dd, 1H, Ar), 6.97 (t,J=0.7.9 Hz, 1H, Ar), 7.13 (dd, J=1.1, 7.7 Hz, 1H, Ar).

5.1.3 2-Bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-benzoic acidmethyl ester

NBS (49.8 g, 280 mmol) was added to methyl 3-(tert-butyldimethylsilyloxy)-2-methylbenzoate (78.4 g, 280 mmol) in methyl acetate(500 mL) at room temperature to give an orange colored suspension. Theresulting reaction mixture was heated in an oil bath at 40° C. andshined by 300 wt sunlight bulb at reflux for 4 hours. The reactionmixture was cooled down and washed by Na₂SO₃ solution (2×600 mL, 50%saturated concentration), water (500 mL) and brine (600 mL). The organiclayer was dried by MgSO₄ and decolorized by charcoal. The organic layerwas concentrated to give2-bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-benzoic acid methylester as a light brown oil (96 g, 91% crude yield). The compound wasused in the next step without further purification: LCMS M-Br=279; ¹HNMR (DMSO-d₆) δ 0.05-0.11 (m, 6H, CH₃, CH₃), 0.82 (s, 9H, CH₃, CH₃,CH₃), 3.65 (s, 3H, CH₃), 4.74 (s, 2H, CH₂), 6.94 (dd, J=1.3, 8.1 Hz, 1H,Ar), 7.10-7.20 (m, 1H, Ar), 7.21-7.29 (m, 1H, Ar).

5.1.4 4-Carbamoyl-Butyric Acid Methyl Ester

To a stirred solution of methyl2-(bromomethyl)-3-(tert-butyldimethylsilyloxy)benzoate (137.5 g, 325mmol) in acetonitrile (1100 mL) in a 2 L round bottom flask, was addedmethyl 4,5-diamino-5-oxopentanoate hydrochloride (70.4 g, 358 mmol). Tothe suspension was added DIPEA (119 ml, 683 mmol) through an additionfunnel over 10 minutes and the suspension was stirred at roomtemperature for 1 hour before the mixture was heated in an oil bath at40° C. for 23 hours. The reaction mixture was concentrated under vacuo.The residue was stirred in ether (600 mL), and a white solidprecipitated out. The mixture was filtered and the solid was washed withether (400 mL). The filtrate was washed with HCl (1N, 200 mL), NaHCO₃(sat. 200 mL) and brine (250 mL). The aqueous acid layer and basic layerwere kept separately. Then the solid was further washed with ether (250mL) and the liquid was washed with above acid solution and basicsolution. The two organic layers were combined and concentrated undervacuo to give4-[4-(tert-Butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as a brown oil (152 g, 115% crude yield, 77% purity byH NMR). The compound was used in the next step without furtherpurification: LCMS MH=407.

5.1.5 4-Carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyricacid methyl ester

To a stirred cold solution of methyl5-amino-4-(4-(tert-butyldimethylsilyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(152 g, 288 mmol) in DMF (500 mL) and water (55 mL), was added by K₂CO₃(19.89 g, 144 mmol) by portions over 5 minutes. The resulting reactionmixture was stirred at room temperature for 40 minutes. The reactionmixture was cooled in an ice bath. To the mixture, HCl (12M, 23.99 ml,288 mmol) was added slowly. After the addition, acetonitrile (280 mL)was added to the mixture and a solid precipitated out. The mixture wasstirred at room temperature for 10 minutes and filtered. The solid waswashed with acetonitrile (50 mL×4). The filtrate was concentrated underhigh vacuo to give a yellow oil (168 g). The oil was dissolved inacetonitrile (600 mL) and stirred at room temperature for 10 minutes.The mixture was filtered and the solid was washed with acetonitrile (25mL×2). The filtrate was concentrated under high vacuo to give a yellowoil (169 g), which was added to a mixture of water (1200 mL) and ether(1000 mL). The mixture was stirred for 3 minutes and the layers wereseparated. The aqueous solution was concentrated under high vacuo andthe residue was stirred in acetonitrile (160 mL) and a white solid wasformed after overnight stirring. The mixture was filtered to give4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester as a white solid (46 g, 54% yield). The filtrate wasconcentrated and the residue was further crystallized in acetonitrile(60 mL) to give more4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester as a white solid (11.7 g, 14% yield). The filtrate wasconcentrated and the residue was purified by ISCO chromatography to givemore 4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyricacid methyl ester as a white solid (13.2 g, 15% yield). The totalproduct obtained was 70.9 g in 83% yield: LCMS MH=293; ¹H NMR (DMSO-d₆)δ 1.95-2.34 (m, 4H, CH₂, CH₂), 3.51 (s, 3H, CH₃), 4.32 (d, J=17.6 Hz,1H, CHH), 4.49 (d, J=17.4 Hz, 1H, CHH), 4.73 (dd, J=4.7, 10.2 Hz, 1H,CHH), 6.99 (dd, J=0.8, 7.9 Hz, 1H, Ar), 7.10-7.23 (m, 2H, Ar, NHH),7.25-7.38 (m, 1H, Ar), 7.58 (s, 1H, NHH), 10.04 (s,

1H, OH).

5.23-[4-(4-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

5.2.1 Procedure 1

Step 1: To the solution of3-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (2.5g, 8.56 mmol) in THF (60 mL) was added triphenyl phosphine (polymersupported 1.6 mmol/g, 12 g, 18.8 mmol). The mixture was stirred at roomtemperature for 15 minutes. Diisopropyl azodicarboxylate (3.96 mL, 18.8mmol) was added at 0° C., and the mixture was stirred at 0° C. for 30minutes. (4-Morpholin-4-ylmethyl-phenyl)-methanol (2.62 g, 12.4 mmol)was added at 0° C., and the mixture was allowed to warm to roomtemperature and stirred at room temperature overnight. The reactionmixture was filtered, and the filtrate was concentrated. The resultingoil was purified on silica gel column eluted with methylene chloride andmethanol (gradient, product came out at 6% methanol) to give4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (2.2 g, 54% yield). The product was used in the nextstep without further purification.

Step 2: To the THF solution (50 mL) of4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (2.2 g, 4.57 mmol) was added potassium tert-butoxide(0.51 g, 4.57 mmol) at 0° C. The mixture was stirred at 0° C. for 10minutes and was quenched with 1N HCl (5 mL, 5 mmol) followed bysaturated NaHCO₃ (25 mL). The mixture was extracted with EtOAc (2×50mL). The organic layer was washed with water (30 mL), brine (30 mL),dried over MgSO₄ and concentrated. To the resulting solid was addedEtOAc (10 mL) followed by hexane (10 mL) under stirring. The suspensionwas filtered to give3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas white solid (1.5 g, 73% yield). HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, gradient to 95/5 acetonitrile/0.1% H₃PO₄in 5 min; t_(R)=4.78 min (97.5%); mp: 210-212° C.; ¹H NMR (DMSO-d₆) δ1.86-2.09 (m, 1H, CHH), 2.29-2.38 (m, 4H, CH₂, CH₂), 2.44 (dd, J=4.3,13.0 Hz, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.82-2.99 (m, 1H, CHH), 3.46(s, 2H, CH₂), 3.52-3.61 (m, 4H, CH₂, CH₂), 4.18-4.51 (m, 2H, CH₂), 5.11(dd, J=5.0, 13.3 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.27-7.38 (m, 5H, Ar),7.40-7.53 (m, 3H, Ar), 10.98 (s, 1H, NH) ¹³C NMR (DMSO-d₆) δ 22.36,31.21, 45.09, 51.58, 53.14, 62.10, 66.17, 69.41, 114.97, 115.23, 127.64,128.99, 129.81, 129.95, 133.31, 135.29, 137.68, 153.50, 168.01, 170.98,172.83; LCMS: 465; Anal Calcd for C₂₅H₂₇N₃O₅+0.86H₂O: C, 64.58; H, 6.23;N, 9.04. Found: C, 64.77; H, 6.24; N, 8.88.

5.2.2 Procedure 2

Step 1: To a 2-L round bottom flask, were charged methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (30 g, 103mmol), 1,4-bis(bromomethyl)benzene (81 g, 308 mmol) and potassiumcarbonate (14.19 g, 103 mmol) and acetonitrile (1.2 L). The mixture wasstirred at room temperature for 10 minutes and heated to 50° C. for 12hours. The reaction mixture was allowed to cool to room temperature. Themixture was filtered and the filtrate was concentrated on rota-vap. Theresulting solid was dissolved in CH₂Cl₂ and loaded on 2 silica gelcolumns (330 g each) and eluted using CH₂Cl₂/MeOH to give4-[4-(4-bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as white solid (40 g, 82% yield): ¹H NMR (DMSO-d₆) δ1.98-2.13 (m, 1H, CHH), 2.14-2.23 (m, 1H, CHH), 2.23-2.32 (m, 2H, CHH,CHH), 3.50 (s, 3H, CH₃), 4.34-4.63 (m, 2H, CH₂), 4.67-4.80 (m, 3H, CH₂,NCH), 5.25 (s, 4H, CH₂), 7.19 (s, 1H, NHH), 7.24-7.34 (m, 2H, Ar),7.41-7.54 (m, 5H, Ar), 7.58 (br. s., 1H, NHH).

Step 2: To the CH₂Cl₂ solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(36.5 g, 77 mmol), was added morpholine (14.72 ml, 169 mmol) at roomtemperature. The mixture was stirred at room temperature for 1 hour. Theresulting suspension was filtered, and the filtrate was concentrated onrota-vap. The resulting oil was dissolved in 350 mL of EtOAc and washedwith water (50 mL×3). The organic layer was concentrated on rota-vap togive4-carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a foamy solid (39 g, 100% yield): ¹H NMR (DMSO-d₆)δ 2.00-2.12 (m, 1H, CHH), 2.14-2.22 (m, 1H, CHH), 2.22-2.29 (m, 2H, CHH,CHH), 2.30-2.39 (m, 4H, CH₂, CH₂), 3.46 (s, 2H, CH₂), 3.50 (s, 3H, CH₃),3.53-3.63 (m, 4H, CH₂, CH₂), 4.28-4.59 (m, 2H, CH₂), 4.73 (dd, J=4.7,10.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.14-7.23 (m, 1H, NHH), 7.26-7.39(m, 4H, Ar), 7.41-7.51 (m, 3H, Ar), 7.58 (s, 1H, NHH).

Step 3: To the THF solution of methyl5-amino-4-(4-(4-(morpholinomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(40 g, 83 mmol), was added potassium 2-methylpropan-2-olate (9.80 g, 87mmol) portion wise at 0° C. The mixture was stirred at this temperaturefor 30 minutes. To the reaction mixture, was added 45 mL of 1N HClsolution, followed by 200 mL of saturated NaHCO₃ solution. The mixturewas diluted with 500 mL of EtOAc at 0° C., stirred for 5 minutes andseparated. The organic layer was washed with water (50 mL×3) and brine(100 mL), and concentrated on rota-vap to give a white solid, which wasstirred in diethyl ether (300 mL) to give a suspension. The suspensionwas filtered to give3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas white solid (28.5 g, 72% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, gradient to 95/5 acetonitrile/0.1% H₃PO₄in 5 min; t_(R)=4.78 min (98.5%); mp: 209-211° C.; ¹H NMR (DMSO-d₆) δ1.86-2.09 (m, 1H, CHH), 2.29-2.38 (m, 4H, CH₂, CH₂), 2.44 (dd, J=4.3,13.0 Hz, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.82-2.99 (m, 1H, CHH), 3.46(s, 2H, CH₂), 3.52-3.61 (m, 4H, CH₂, CH₂), 4.18-4.51 (m, 2H, CH₂), 5.11(dd, J=5.0, 13.3 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.27-7.38 (m, 5H, Ar),7.40-7.53 (m, 3H, Ar), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.36,31.21, 45.09, 51.58, 53.14, 62.10, 66.17, 69.41, 114.97, 115.23, 127.64,128.99, 129.81, 129.95, 133.31, 135.29, 137.68, 153.50, 168.01, 170.98,172.83; LCMS: 465; Anal Calcd for C₂₅H₂₇N₃O₅+0.86H₂O: C, 64.63; H, 6.22;N, 9.04; Found: C, 64.39; H, 6.11; N, 8.89; H₂O, 3.24.

5.33-{4-[4-(2,2,3,3,4,4,5,5,6,6-DECADEUTERO-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: Perdeutero-piperidine (d₁₁, 98% D, 136 mg, 1.42 mmol) was addedto a solution of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(450 mg, 0.95 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.42 mmol)in dry MeCN (9 mL). The reaction mixture was warmed up to 60° C. withstirring for 2 hours. The mixture was allowed to cool down to roomtemperature and then stored at 4° C. overnight. A solid formed uponcooling and the slurry was partitioned between EtOAc (150 mL) and 1NNaHCO₃ (40 mL). The aqueous layer was washed with EtOAc (100 mL) and thecombined organic layer was washed with brine, dried (Na₂SO₄), andconcentrated in vacuo to provide4-carbamoyl-2-{4-[4-(2,2,3,3,4,4,5,5,6,6-decadeutero-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid tert-butyl ester as a white solid (490 mg, 97% yield): LCMS MH=532.The solid was used in the next step without further purification.

Step 2: To a solution of4-carbamoyl-2-{4-[4-(2,2,3,3,4,4,5,5,6,6-decadeutero-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid tert-butyl ester (490 mg, 0.92 mmol) in THF (10 mL) at roomtemperature, was added KOtBu (109 mg, 0.96 mmol) as a solid in oneportion. The solution changed color from pale to a deep yellow uponaddition, and the mixture was stirred at room temperature for about 30minutes. More KOtBu (14 mg) was added to the reaction and stirring wascontinued overnight. After about 17 hours, added another portion ofKOtBu (28 mg), and the reaction was allowed to stir at room temperaturefor an additional 2 hours. The reaction mixture was quenched with aceticacid (0.158 mL, 2.76 mmol) at 0° C. The resulting slurry wasconcentrated in vacuo and the residue partitioned between EtOAc (75 mL)and 1N NaHCO₃ (30 mL). The aqueous layer was washed with more EtOAc (75mL). The combined organic layers was washed with brine, dried (Na₂SO₄),and concentrated in vacuo to give a tan solid. Et₂O (20 mL) was added tothe solid crude product and the slurry was triturated by sonication,followed by filtration and washing of the solid with additional Et₂O.The cake was suction dried to give3-{4-[4-(2,2,3,3,4,4,5,5,6,6-Decadeutero-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a pale yellow solid (205 mg, 49% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 5% grad 95% in 5 min,acetonitrile/0.1% H₃PO₄, 4.69 min (95.6%); mp: 186-188° C.; ¹H NMR(DMSO-d₆) δ 1.88-2.06 (m, 1H, CHH), 2.37-2.48 (m, 1H, CHH), 2.52-2.63(m, 1H, CHH), 2.81-3.02 (m, 1H, CHH), 3.41 (s, 2H, CH₂), 4.25 (d, J=17.6Hz, 1H, CHH), 4.41 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.1 Hz,1H, CH), 5.22 (s, 2H, CH₂), 7.26-7.37 (m, 4H, Ar), 7.38-7.57 (m, 3H,Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 31.18, 45.07, 51.55,62.42, 69.42, 114.94, 115.19, 127.57, 128.78, 129.78, 129.93, 133.28,135.00, 138.58, 153.51, 167.99, 170.95, 172.80; CD₂ carbon signals arenot observed in the ¹³C NMR; LCMS MH=458; Anal Calcd forC₂₆H₁₉D₁₀N₃O₄+0.25H₂O: C, 67.58; H, 6.43; N, 9.09; Found: C, 67.51; H,6.32; N, 9.16.

5.43-{4-[4-(2,2,3,3,5,5,6,6-OCTADEUTERO-MORPHOLIN-4-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To a solution of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(450 mg, 0.95 mmol) and N,N-diisopropylethylamine (0.24 mL, 1.42 mmol)in MeCN (9 mL), was added 2,2,3,3,5,5,6,6-octadeutero-morpholine (d₈,98% D, 136 mg, 1.42 mmol). The reaction was stirred at 60° C. for 2.5hours. The mixture (a white slurry) was concentrated to dryness and thesolid residue was partitioned between EtOAc (150 mL) and 1N NaHCO₃ (35mL). The aqueous layer was washed with additional EtOAc (150 mL). Theorganic layers were combined, washed with brine, dried (Na₂SO₄), andconcentrated in vacuo to provide4-carbamoyl-2-{4-[4-(2,2,3,3,5,5,6,6-octadeutero-morpholin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid tert-butyl ester as a white solid (0.5 g, 99% yield): LCMS MH=532.The solid was used in the next step without

Step 2: To a cooled solution of4-carbamoyl-2-{4-[4-(2,2,3,3,5,5,6,6-octadeutero-morpholin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid tert-butyl ester (0.5 g, 0.94 mmol) in THF (10 mL) at 0° C., wasadded KOtBu (0.137 g, 1.22 mmol) as a solid in one portion. The solutionturned deep yellow. The ice bath was immediately removed and thereaction mixture was stirred at room temperature for about 90 minutes.The mixture was cooled in an ice bath and quenched by addition of aceticacid (0.162 mL, 2.82 mmol).

The volatiles were removed in vacuo to give a white solid that waspartitioned between EtOAc (125 mL) and 1N NaHCO₃ (30 mL). The aqueouslayer was washed with additional EtOAc (about 75 mL). The EtOAc layerswere combined, washed with brine, dried (Na₂SO₄), and concentrated invacuo to give 400 mg of a solid. This white solid was slurried in Et₂O(25 mL) and vigorously vortexed and sonicated to aid with trituration.The slurry was then filtered and suction dried on filter funnel forabout ½ hour. The cake was stored in a vacuum oven at 60° C. for severalhours to give3-{4-[4-(2,2,3,3,5,5,6,6-Octadeutero-morpholin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (236 mg, 55% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 5% grad 95% in 10 min, acetonitrile/0.1%H₃PO₄, 5.55 min (96.5%); mp: 206-208° C.; ¹H NMR (DMSO-d₆) δ 1.88-2.07(m, 1H, CHH), 2.34-2.49 (m, 1H, CHH), 2.52-2.65 (m, 1H, CHH), 2.80-3.01(m, 1H, CHH), 3.46 (s, 2H, CH₂), 4.25 (d, J=17.6 Hz, 1H, CHH), 4.41 (d,J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.2, 13.1 Hz, 1H, CH), 5.23 (s, 2H,CH₂), 7.23-7.38 (m, 4H, Ar), 7.39-7.54 (m, 3H, Ar), 10.97 (s, 1H, CH);¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 45.06, 51.55, 62.01, 69.38, 114.96,115.20, 127.61, 128.97, 129.78, 129.93, 133.28, 135.25, 137.72, 153.48,167.99, 170.96, 172.81; CD2 carbon signals are not observed due tocoupling and splitting with deuteriums; LCMS MH=458; Anal Calcd forC₂₅H₁₉D₈N₃O₅+0.25H₂O: C, 64.98; H, 6.00; N, 9.09; Found: C, 64.91; H,5.71; N, 9.04.

5.53-[4-(2-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the THF solution (15 mL) of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.3 g, 1 mmol), was added triphenyl phosphine resin (1.38g, 2.2 mmol/g loading, 2.2 mmol) and DIAD (0.43 mL, 2.2 mmol) at 0° C.,and kept for 10 minutes. To the mixture was added(2-morpholin-4-ylmethyl-phenyl)-methanol (0.31 g, 1.5 mmol), and themixture was stirred at room temperature overnight. The mixture wasfiltered and the filtrate was concentrated and extracted with EtOAc (30mL) and Na₂CO₃ (20 mL). The organic layer was washed with water (20 mL),brine (20 mL), and concentrated. The resulting oil was purified onsilica gel column to give4-carbamoyl-4-[4-(2-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.07 g, 15% yield).

Step 2: To the THF solution (20 mL) of4-carbamoyl-4-[4-(2-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.07 g, 0.15 mmol), was added potassium t-butoxide(20 mg, 0.18 mmol) at 0° C. The mixture was stirred for 15 minutes at 0°C. and quenched with 5 mL of 1N HCl solution, followed by 15 mL ofsaturated NaHCO₃ solution. The mixture was extracted with EtOAc (20 mL).The organic layer was concentrated in vacuo. The resulting oil waspurified on silica gel column eluted with CH₂Cl₂ and methanol to give3-[4-(2-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (30 mg, 50% yield): mp: 188-190° C.; HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradientacetonitrile/0.1% H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at100/0 for 5 min: t_(R)=4.8 min (96%). ¹H NMR (DMSO-d₆) δ 1.84-2.11 (m,1H, CHH), 2.22-2.44 (m, 5H, CHH, CH₂CH₂), 2.54-2.64 (m, 1H, CHH), 2.89(d, J=12.5 Hz, 1H, CHH), 3.42-3.62 (m, 6H, CH₂CH₂, CH₂), 4.17-4.52 (m,2H, CH₂), 5.12 (dd, J=5.0, 13.1 Hz, 1H, NCH), 5.43 (s, 2H, CH₂),7.17-7.40 (m, 5H, Ar), 7.42-7.65 (m, 2H, Ar), 10.97 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 0.03, 22.29, 31.13, 45.05, 51.52, 53.13, 60.10, 66.15,67.17, 114.77, 115.09, 127.29, 127.54, 127.90, 129.76, 130.08, 133.25,135.62, 135.75, 153.46, 167.94, 170.91, 172.75; LCMS MH=450; Anal Calcdfor C₂₅H₂₇N₃O₅+0.2H₂O: C, 66.27; H, 6.10; N, 9.27; Found: C, 66.06% H,5.85; N, 9.14%.

5.63-[4-(3-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the THF (10 mL) solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (1.0 g, 3.42 mmol), were added triphenyl phosphine resin(2.3 g, 2.2 mmol/g loading, 6.84 mmol) and DIAD (1.33 mL, 6.84 mmol) at0° C. and kept for 10 minutes. To the mixture was added(3-morpholin-4-ylmethyl-phenyl)-methanol (1.06 g, 3.42 mmol) and stirredat room temperature overnight. The mixture was filtered and the filtratewas concentrated and extracted with EtOAc (30 mL) and Na₂CO₃ (20 mL).The organic layer was washed with water (20 mL) and brine (20 mL), andconcentrated. The resulting oil was purified on silica gel column togive4-carbamoyl-4-[4-(3-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.50 g, 30%).

Step 2: To the THF solution (20 mL) of4-carbamoyl-4-[4-(3-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.3 g, 0.6 mmol), was added potassium t-butoxide (0.6mL g, 0.6 mmol) at 0° C. The mixture was stirred for 15 minutes at 0° C.and quenched with 5 mL of 1N HCl solution followed by 15 mL of saturatedNaHCO₃ solution. The mixture was extracted with EtOAc (20 mL). Theorganic layer was concentrated in vacuo. The resulting oil was purifiedon silica gel column eluted with CH₂Cl₂ and methanol to give3-[4-(3-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (120 mg, 44% yield): mp: 247-249° C.; HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradientacetonitrile/0.1% H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at100/0 for 5 min: t_(R)=4.8 min (96%); ¹H NMR (DMSO-d₆) δ 1.93-2.03 (m,1H, CHH), 2.26-2.38 (m, 4H, CH₂, CH₂), 2.40-2.48 (m, 1H, CHH), 2.54-2.63(m, 1H, CHH), 2.84-2.98 (m, 1H, CHH), 3.48-3.59 (m, 4H, CH₂, CH₂),4.20-4.48 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.4 Hz, 1H, NCH), 5.25 (s, 2H,CH₂), 7.24-7.42 (m, 6H, Ar), 7.44-7.51 (m, 1H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.36, 31.20, 45.10, 51.59, 53.11, 62.21, 66.16,69.58, 115.20, 115.27, 126.37, 128.09, 128.38, 128.53, 129.79, 129.98,133.31, 136.54, 138.06, 153.44, 167.99, 170.98, 172.85; LCMS MH=450;Anal Calcd for C₂₅H₂₇N₃O₅+0.4H₂O: C, 65.75; H, 6.14; N, 9.20; Found: C,65.38% H, 5.95; N, 9.21.

5.7 3-(1-OXO-4-(4-(2-(PYRROLIDIN-1-YL)ETHOXY)BENZYLOXY)ISOINDOLIN-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of 4-hydroxybenzaldehyde (4.0 g, 32.8 mmol) an Cs₂O₃(26.7 g, 81.9 mmol) in DMF (80 mL) was stirred for 10 minutes at roomtemperature. To this mixture, was added 1-(2-chloroethyl)pyrrolidinehydrochloride (6.7 g, 39.3 mmol). The mixture was warmed at 60° C. for 2hours then at 80° C. overnight. The reaction mixture was cooled andfiltered, and the solid was washed with EtOAc (100 mL). The filtrate wasstirred with cold water (200 mL) and the aqueous layer was extractedwith EtOAC (3×50 mL). The combined EtOAc solutions was washed with 2NNaOH (40 mL), water (3×40 mL) and brine (40 mL) and dried (K₂CO₃). Thesolvent was removed to give 4-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde(5.9 g, 81% yield): ¹H NMR (CDCl₃) δ 1.76-1.84 (m, 4H), 2.60-2.65 (m,4H), 2.91-2.95 (m, 2H), 4.19 (t, J=6.0 Hz, 2H), 7.00-7.04 (m, 2H),7.80-7.95 (m, 2H), 9.88 (s, 1H).

Step 2: A solution of 4-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde (5.8 g,26.5 mmol) in reagent alcohol (60 mL) was cooled to −60° C. in dryice/acetone bath. LiBH4/THF (2M, 15.9 mL, 31.9 mmol) was added slowly at−60° C. The mixture was stirred at −60° C. for 1 hour. The reactionmixture was quenched with water (20 mL) slowly and then warmed to roomtemperature. The mixture was concentrated and the residue was stirredwith EtOAc (80 mL) and 2N NaOH (20 mL). The aqueous layer was extractedwith EtOAc (2×30 mL), and the combined EtOAc solutions was washed withwater (30 mL) and brine (30 mL) and dried. The solvent was removed andthe residue was purified by chromatography (SiO₂, NH₄OH:CH₃OH:CH₂Cl₂0.5:3:97) to give 4-[(2-pyrrolidin-1-yl-ethoxy)-phenyl]-methanol (2.5 g,42% yield): ¹H NMR (CDCl₃) δ 1.74-1.83 (m, 4H), 2.56-2.63 (m, 4H), 2.86(t, J=6.1 Hz, 2H), 4.03 (t, J=6.0 Hz, 2H), 4.57 (s, 2H), 6.82-6.87 (m,2H), 7.23-7.27 (m, 2H).

Step 3: Diisopropyl azodicarboxylate (1.1 g, 5.5 mmol) was added slowlyto a stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol), 4-[(2-pyrrolidin-1-yl-ethoxy)-phenyl]-methanol (0.9 g, 4.1 mmol)and triphenylphosphine-polymer bound (1.8 g, 5.5 mmol) in THF (60 mL) at5-8° C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and the solid was washedwith CH₂Cl₂ (30 mL). The filtrate was concentrated and the residue waspurified by chromatography (SiO₂, CH₃OH: CH₂Cl₂=3:97) to give methyl5-amino-5-oxo-4-(-oxo-4-(4-(2-pyrrolidin-1-yl)ethoxy)benzyloxy)isoindolin-2-yl)pentanoate(1.0 g, 77%).

Step 4: A solution of KO-t-Bu/THF (1M, 2.5 mL, 2.5 mmol) was addedslowly to a stirred solution of methyl5-amino-5-oxo-4-(1-oxo-4-(4-(2-pyrrolidin-1-yl)ethoxy)benzyloxy)isoindolin-2-yl)pentanoate(1.0 g, 2.1 mmol) in THF (30 mL) at 5° C. The mixture was stirred at 5°C. for 10 minutes then warmed to room temperature for 2 hours. Thereaction mixture was cooled in an ice bath and quenched with 4N HCl (4mL). The mixture was stirred with EtOAc (40 mL) and sat Na₂CO₃ (25 mL).The aqueous layer was extracted with EtOAc (3×40 mL) and combined EtOAcsolution was washed with water (40 mL) and brine (40 mL) and dried(K₂CO₃). The solvent was removed and the residue was purified bychromatography (SiO₂, CH₃OH:CH₂Cl₂=5:95) to give3-(1-oxo-4-(4-(2-pyrrolidin-1-yl)ethoxy)-benzyloxy)isoindolin-2-yl)piperidine-2,6-dione(0.2 g, 20% yield): mp 153-155° C.; 1H NMR (DMSO-d6) δ 1.66-1.69 (m,4H), 1.94-1.99 (m, 1H), 2.40-2.59 (m, 2H), 2.77 (t, J=5.7 Hz, 2H),2.84-2.90 (m, 1H), 4.06 (t, J=6.0 Hz, 2H), 4.24 (d, J=17.4 Hz, 1H), 4.35(d, J=17.7 Hz, 1H), 5.07-5.13 (dd, J=5.1 and 13.2 Hz, 1H), 5.15 (s, 2H),6.92-6.97 (m, 2H), 7.30-7.50 (m, 5H), 10.96 (s, 1H); 13C NMR (DMSO-d6) δ22.33, 23.09, 31.17, 45.06, 51.54, 53.93, 54.24, 66.69, 69.34, 114.35,115.04, 115.12, 128.42, 129.50, 129.75, 129.95, 133.25, 153.50, 158.33,168.00, 170.96, 172.81; Calcd for C₂₆H₂₉N₃O₅+0.5 Et2O: C, 66.65; H,6.63; N, 8.64; Found: C, 66.95; H, 6.62; N, 8.71.

5.83-[4-(3-CHLORO-4-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To a round bottom flask, were charged 3-chloro-4-methyl-benzoicacid (1.5 g, 9 mmol) and trimethyl orthoacetate (25 mL). The mixture washeated at 100° C. overnight. The reaction mixture was concentrated invacuo. The resulting oil, 3-chloro-4-methyl-benzoic acid methyl ester,was used in next step without purification.

Step 2: To the CCl₄ solution (50 mL) of 3-chloro-4-methyl-benzoic acidmethyl ester (1.66 g, 0.9 mmol), was added NBS (1.58 g, 9 mol). Thesuspension was bathed in the light of 300-W sun lamp and heated at 65°C. for 1 hour. The mixture was filtered and the filtrate wasconcentrated in vacuo. The resulting oil, 4-bromomethyl-3-chloro-benzoicacid methyl ester, was used in next step without further purification.

Step 3: To the acetonitrile solution (30 mL) of4-bromomethyl-3-chloro-benzoic acid methyl ester, was added morpholine(3 mL). The mixture was stirred at room temperature for 0.5 hour andconcentrated on rota-vap. The resulting oil was extracted with EtOAc (30mL) and water (20 mL). The organic layer was concentrated and purifiedon silica gel column eluted with EtOAc and hexane to give3-chloro-4-morpholin-4-ylmethyl-benzoic acid methyl ester (1.0 g, 42%for three steps) as yellow oil.

Step 4: To the THF solution (30 mL) of3-chloro-4-morpholin-4-ylmethyl-benzoic acid methyl ester (1.0 g, 3.7mmol), was added LiAlH₄ (3.7 mL, 1M in THF, 3.7 mmol) dropwise at 0° C.The mixture was stirred at 0° C. for 30 minutes. The reaction mixturewas quenched with sat. NaHCO₃ (5 mL), and then was diluted with EtOAc(30 mL) and water (20 mL). After extraction, the organic layer wasconcentrated and purified on silica gel column eluted with EtOAc andhexane to give (3-chloro-4-morpholin-4-ylmethyl-phenyl)-methanol as anoil (0.6 g, 70%).

Step 5: To the THF solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.32 g, 1.1 mmol), was added triphenyl phosphine resin(1.94 g, 1.6 mmol/g loading, 2.42 mmol) and DIAD (0.477 mL, 2.42 mmol)at 0° C. After being stirred at 0° C. for 10 minutes, to the mixture wasadded (3-chloro-4-morpholin-4-ylmethyl-phenyl)-methanol (0.40 g, 1.66mmol). The mixture was stirred at room temperature overnight. Themixture was filtered and the filtrate was concentrated and extractedwith EtOAc (30 mL) and Na2CO3 (20 mL). The organic layer was washed withwater (20 mL) and brine (20 mL), and concentrated. The resulting oil waspurified on silica gel column to give4-carbamoyl-4-[4-(3-chloro-4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.40 g, 73%).

Step 6: To the THF solution (20 mL) of4-carbamoyl-4-[4-(3-chloro-4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.64 g, 1.2 mmol), was added potassium t-butoxide(0.14 g, 1.2 mmol) at 0° C. The mixture was stirred for 15 minutes at 0°C. and quenched with 5 mL of 1N HCl solution, followed by 15 mL ofsaturated NaHCO₃ solution. The mixture was extracted with EtOAc (20 mL).The organic layer was concentrated in vacuo. The resulting solid wasstirred in MeOH (5 ml) and filtered to give3-[4-(3-chloro-4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione(300 mg, 50%) as white solid: mp: 240-242° C. HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1%H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R)=4.81 min (96%); ¹H NMR (DMSO-d₆) δ 1.86-2.10 (m, 1H, CHH),2.37-2.45 (m, 5H, CH₂, CH₂, CHH), 2.54-2.63 (m, 1H, CHH), 2.84-2.99 (m,1H, CHH), 3.42-3.69 (m, 6H, CH₂, CH₂, CH₂), 4.07-4.58 (m, 2H, CHH),4.98-5.17 (m, 1H, NCH), 5.25 (s, 2H, CH₂), 7.22-7.38 (m, 2H, Ar),7.40-7.61 (m, 4H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.26,31.10, 44.99, 51.49, 53.10, 58.68, 66.09, 68.38, 114.86, 115.31, 126.13,128.22, 129.75, 129.88, 130.91, 133.23, 133.32, 134.85, 137.37, 153.19,167.86, 170.88, 172.75; LCMS MH=484; Anal Calcd for C₂₅H₂₆N₃O₅Cl: C,62.05; H, 5.42; N, 8.68; Found: C, 61.71; H, 5.08; N, 8.62.

5.93-(4-(4-(2-MORPHOLIN-4-YL-ETHOXY)-BENZYLOXY)-1-OXOISOINDOLIN-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of 4-hydroxybenzaldehyde (4.0 g, 32. mmol) and Cs₂CO₃(26.7 g, 81.9 mmol) in DMF (80 mL) was stirred at room temperature for10 minutes. To this mixture was added 4-(2-chloroethyl)morpholinehydrochloride (7.3 g, 39.3 mmol). The resulting mixture was heated at80° C. in an oil bath overnight. The reaction mixture was cooled to roomtemperature and filtered, and the solid was washed with EtOAc (100 mL).Filtrate was diluted with cold water (200 mL) and aqueous layer wasextracted with EtOAc (3×50 mL). Combined EtOAc solution was washed with2N NaOH (25 mL), water (3×40 mL) and brine (40 mL), and dried (K₂CO₃).The solvent was removed to give 4-(2-morpholin-4-yl-ethoxy)-benzaldehyde(6.2 g, 81% yield): ¹H NMR (CDCl₃) δ 2.57-2.60 (m, 4H), 2.83 (t, J=5.7Hz, 2H), 3.70-3.75 (m, 4H), 4.19 (t, J=5.7 Hz, 2H), 6.98-7.03 (m, 2H),7.81-7.85 (m, 2H), 9.88 (s, 1H); ¹³C NMR (CDCl₃) δ 53.52, 56.73, 65.77,66.11, 114.93, 129.58, 131.73, 163.40, 191.21.

Step 2: LiBH₄/THF (2M, 15.9 mL, 31.7 mmol) was added slowly to a stirredsolution of 4-(2-morpholin-4-yl-ethoxy)-benzaldehyde (6.2 g, 26.4 mmol)in reagent alcohol (60 mL) at −60° C. The resulting mixture was stirredat −60° C. for 1 hour then quenched with water (20 mL). The mixture wasconcentrated and the residue was stirred with EtOAc (80 mL) and 1N NaOH(30 mL). The aqueous layer was extracted with EtOAc (2×30 mL) andcombined EtOAc solution was washed with water (40 mL) and brine (40 mL)and dried. The solvent was removed and the residue was purified bychromatography (SiO₂, NH₄OH: CH₃OH: CH₂Cl₂ 0.5:3:100) to give[4-(2-morpholin-4-yl-ethoxy)-phenyl]-methanol (4.2 g, 67% yield): ¹H NMR(CDCl₃) δ 2.25 (s, 1H), 2.54-2.57 (m, 4H), 2.78 (t, J=5.7 Hz, 2H),3.70-3.73 (m, 4H), 4.08 (t, J=5.7 Hz, 2H), 4.59 (s, 2H), 6.85-6.89 (m,2H), 7.25-7.29 (m, 2H); ¹³C NMR (CDCl₃) δ 54.06, 57.61, 65.79, 66.85,114.62, 128.57, 133.52, 158.24.

Step 3: Triphenylphosphine-polymer bound (1.8 g, 5.5 mmol) was stirredwith dry CH₂Cl₂ (20 mL) for 10 minutes. To this mixture was added asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol) and [4-(2-morpholin-4-yl-ethoxy)-phenyl]-methanol (1.0 g, 4.1mmol) in THF (60 mL). The resulting mixture was cooled to 5° C. anddiisopropyl azodicarboxylate (1.1 g, 5.5 mmol) was added slowly at 5-8°C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and solid was washed withCH₂Cl₂ (30 mL). Filtrate was concentrated and the residue was purifiedby chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-(4-(2-morpholinoethoxy)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxo-pentanoate(1.0 g, 71%).

Step 4: A solution of potassium t-butoxide/THF (1M, 2.6 mL, 2.6 mmol)was added slowly at 5° C. to a stirred solution of methyl5-amino-4-(4-(4-(2-morpholinoethoxy)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.1 g, 2.1 mmol) in THF (30 mL). The reaction mixture was stirred at 5°C. for 10 minutes then warmed to room temperature for 2 hours. Thereaction mixture was cooled in an ice bath and quenched with 4N HCl (4mL). The mixture was stirred with EtOAc (40 mL) and sat. Na₂CO₃ (25 mL).The aqueous layer was extracted with EtOAc (3×40 mL) and combined EtOAcsolution was washed with water (40 mL) and brine (40 mL), and dried(K₂CO₃). The solvent was removed and the residue was purified bychromatography (Al₂O₃, CH₃OH: CH₂Cl₂ 3: 97) to3-(4-(4-(2-morpholinoethoxy)-benzyloxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione(0.2 g, 16% yield): mp: 203-205° C.; ¹H NMR (DMSO-d₆) δ 1.90-2.05 (m,1H), 2.40-2.70 (m, 8H), 2.84-2.96 (m, 1H), 3.55-3.58 (m, 4H), 4.06-4.10(m, 2H), 4.24 (d, J=17.4 Hz, 1H), 4.35 (d, J=17.4 Hz, 1H), 5.07-5.15 (m,3H), 6.97 (d, J=8.4 Hz, 2H), 7.30-7.5.0 (m, 5H), 10.96 (s, 1H); ¹³C NMR(DMSO-d₆) δ 22.32, 31.17, 45.06, 51.55, 53.56, 56.92, 65.29, 66.11,63.31, 114.41, 115.04, 115.11, 128.50, 129.47, 129.74, 129.94, 133.25,153.49, 158.27, 167.99, 170.94, 172.80; Calcd for C₂₆H₂₉N₃O₆+0.2H₂O: C,64.64; H, 6.10; N, 8.70; Found: C, 64.54; H, 6.06; N, 8.63.

5.103-[4-(3-FLUORO-4-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To a stirred solution of 3-fluoro-4-methyl-benzoic acid methylester (5.45 g, 32.4 mmol) in carbon tetrachloride (30 mL), was addedN-bromosuccinimide (5.48 g, 30.8 mmol). The mixture was heated to 80°C., with a 300 W light shined. The mixture was heated for two hours andthen filtered. The filtrated was evaporated to give4-bromomethyl-3-fluoro-benzoic acid methyl ester as a light green oil(9.1 g, 113% crude yield).

Step 2: Morpholine (28.3 mL, 324.4 mmol) was added to a stirred solutionof 4-bromomethyl-3-fluoro-benzoic acid methyl ester (8.01 g, 32.4 mmol)in acetonitrile (40 mL) at room temperature. The mixture was stirred forten minutes and the solvent was evaporated. To the residue was addedwater (40 mL), and then the mixture was extracted with ethyl acetate(3×50 mL). The combined organic phases were evaporated and purified onsilica gel column (EtOAc/Hexanes gradient from 10% to 40% in 40 min) togive 3-fluoro-4-morpholin-4-ylmethyl-benzoic acid methyl ester as ayellow solid (5.58 g, 68% yield): ¹H NMR (DMSO-d₆) δ 2.35-2.44 (m, 4H,CH₂, CH₂), 3.53-3.65 (m, 6H, CH₂, CH₂, CH₂), 3.87 (s, 3H, CH₃),7.55-7.63 (m, 1H, Ar), 7.63-7.70 (m, 1H, Ar), 7.75-7.82 (m, 1H, Ar); ¹³CNMR (DMSO-d₆) δ 52.36, 52.98, 53.22, 54.64, 65.84, 66.10, 66.35, 115.45,115.75, 124.97, 129.95, 130.16, 130.44, 130.54, 131.72, 131.78, 158.73,162.00, 165.09.

Step 3: Lithium aluminum hydride (1.0 M in THF, 8.06 mL, 8.06 mmol) wasadded to a stirred solution of 3-fluoro-4-morpholin-4-ylmethyl-benzoicacid methyl ester (1.02 g, 4.03 mmol) in THF (20 mL) at 0° C. It wasstirred for 30 minutes and quenched with dropwise addition of saturatedsodium bicarbonate. To the mixture was added water (30 mL), and themixture was extracted by ethyl acetate (3×100 mL). The resultingprecipitate was filtered. The combined ethyl acetate filtrate wasevaporated and purified on silica gel column (EtOAc/Hexanes gradientfrom 20% to 90% in 35 min) to give(3-fluoro-4-morpholin-4-ylmethyl-phenyl)-methanol as an oily solid (0.81g, 89% yield): ¹H NMR (DMSO-d₆) δ 2.31-2.42 (m, 4H, CH₂, CH₂), 3.46-3.50(m, 2H, CH₂), 3.51-3.59 (m, 4H, CH₂, CH₂), 4.49 (br. s., 2H, CH₂), 5.27(br. s., 1H, OH), 7.04-7.14 (m, 2H, Ar), 7.29-7.38 (m, 1H, Ar); ¹³C NMR(DMSO-d₆) δ2.89, 54.80, 62.02, 66.13, 112.63, 112.93, 121.80, 121.96,122.17, 131.31, 131.38, 144.40, 144.50, 159.14, 162.38.

Step 4: Polymer-supported triphenylphosphene (1.6 mmol/g, 1.60 g, 2.60mmol) was added to a stirred suspension of(3-fluoro-4-morpholin-4-ylmethyl-phenyl)-methanol (0.39 g, 1.71 mmol) inTHF (20 mL) at 0° C., followed by addition of diisopropyldiazene-1,2-dicarboxylate (0.37 ml, 1.88 mmol). After stirring for 30minutes,4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.50 g, 1.71 mmol) was added. The mixture was stirred forthree hours then filtered, washed with MeOH (3×20 mL) and methylenechloride (3×20 mL). The combined filtrate was evaporated in vacuo togive an oil, which was purified on silica gel column (MeOH/CH₂Cl₂gradient from 1% to 5% in 40 min) to give4-carbamoyl-4-[4-(3-fluoro-4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a clear oil (0.54 g, 63% yield).

Step 5: Potassium tert-butoxide (0.12 g, 1.08 mmol) was added to astirred solution of4-carbamoyl-4-[4-(3-fluoro-4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.54 g, 1.08 mmol) in THF (15 mL) at 0° C. Themixture was stirred for ten minutes and quenched with 1N HCl (3 mL),neutralized by saturated sodium bicarbonate (4 mL to pH=7), and quicklyextracted by ethyl acetate (2×30 mL). The combined ethyl acetate phaseswere evaporated and purified on silica gel column (MeOH/CH₂Cl₂, gradientfrom 1% to 5% in 90 min) to give3-[4-(3-fluoro-4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (0.36 g, 72% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄), 4.90 min(97.8%); mp: 263-265° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.05 (m, 1H, CHH),2.32-2.48 (m, 5H, CHH, CH₂CH₂), 2.54-2.65 (m, 1H, CHH), 2.82-3.02 (m,1H, CHH), 3.47-3.61 (m, 6H, CH₂CH₂, CH₂), 4.23-4.50 (m, 2H, CH₂), 5.12(dd, J=5.2, 13.3 Hz, 1H, NCH), 5.25 (s, 2H, CH₂), 7.25-7.56 (m, 6H, Ar),10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.36, 31.20, 45.09, 51.59,52.93, 54.74, 66.13, 68.56, 114.09, 114.40, 114.92, 115.39, 123.22,123.70, 123.89, 129.84, 130.00, 131.69, 131.75, 133.37, 138.16, 138.26,153.28, 159.08, 162.33, 167.98, 170.96, 172.83; LCMS MH=468; Anal. Calcdfor C₂₅H₂₆N₃O₅F: C, 64.23; H, 5.61; N, 8.99; Found: C, 63.95; H, 5.41;N, 8.92.

5.113-{4-[4-(2-MORPHOLIN-4-YL-ETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To the THF solution of 4-(2-bromoethyl)benzoic acid (25 g, 109mmol) and trifluoroborane etherate (13.71 ml, 109 mmol), was addedborane (196 ml, 196 mmol) dropwise through a dripping funnel at 0° C.during 2 hours. The mixture was stirred at room temperature overnight,and MeOH was added dropwise at room temperature until the cloudysuspension become clear and no more bubbles formed. The clear solutionwas concentrated on rota-vap and the resulting solid was stirred inwater (100 mL) for 30 minutes at room temperature. The suspension wasfiltered to give 4-(2-chloro-ethyl)-benzoic acid as white solid (25 g,107%).

Step 2: To the acetonitrile solution of (4-(2-bromoethyl)phenyl)methanol(25 g, 116 mmol), was added morpholine (25.3 ml, 291 mmol). NaI wasadded all at once. The mixture was stirred at room temperatureover-weekend. The reaction suspension was filtered. The filtrate wasconcentrated and stirred in ether (100 mL) at room temperature for 30minutes. The suspension was filtered. The resulting solid was dissolvedin 1N HCl and was extracted with EtOAc (50 mL×2). The aqueous layer wasneutralized with 1N NaOH to pH=7-8. The resulting suspension wasfiltered to give [4-(2-morpholin-4-yl-ethyl)-phenyl]-methanol as whitesolid (13 g, 60%).

Step 3: To the THF solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.5 g, 1.7 mmol), was added triphenyl phosphine resin (2.3g, 1.6 mmol/g loading, 3.74 mmol) and DIAD (0.73 mL, 3.74 mmol) at 0° C.After being stirred at 0° C. for 10 minutes, the mixture was added[4-(2-morpholin-4-yl-ethyl)-phenyl]-methanol (0.65 g, 2.94 mmol) and wasstirred at room temperature overnight. The mixture was filtered and thefiltrate was concentrated and extracted with EtOAc (30 mL) and Na2CO3(20 mL). The organic layer was washed with water (20 mL) and brine (20mL), and concentrated. The resulting oil was purified on silica gelcolumn to give4-carbamoyl-4-{4-[4-(2-morpholin-4-yl-ethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as white solid (0.74 g, 88%).

Step 4: To the THF solution (20 mL) of4-carbamoyl-4-{4-[4-(2-morpholin-4-yl-ethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester (0.74 g, 1.5 mmol) was added potassium t-butoxide(0.16 g, 1.5 mmol) at 0° C. The mixture was stirred for 15 minutes at 0°C. and quenched with 5 mL of 1N HCl solution followed by 15 mL ofsaturated NaHCO₃ solution. The mixture was extracted with EtOAc (20 mL).The organic layer was concentrated in vacuo. The resulting oil waspurified on silica gel column eluted with CH₂Cl₂ and methanol to give3-{4-[4-(2-morpholin-4-yl-ethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (620 mg, 87% yield): mp: 230-232° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradientacetonitrile/0.1% H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at100/0 for 5 min: t_(R)=4.86 min (97%); ¹H NMR (DMSO-d₆) δ 1.80-2.12 (m,1H, CHH), 2.40-2.44 (m, 4H, CH₂, CH₂), 2.45-2.48 (m, 1H, CHH), 2.55-2.64(m, 1H, CHH), 2.69-2.80 (m, 2H, CH₂), 2.81-3.00 (m, 1H, CHH), 3.52-3.61(m, 4H, CH₂, CH₂), 4.18-4.48 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H,NCH), 5.20 (s, 2H, CH₂), 7.19-7.54 (m, 7H, Ar), 10.97 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 22.36, 31.21, 32.04, 45.10, 51.58, 53.21, 59.93, 66.13,69.47, 114.98, 115.19, 127.80, 128.70, 128.74, 129.79, 129.95, 133.29,134.08, 140.25, 153.50, 168.01, 170.96, 172.82; LCMS MH=464; Anal Calcdfor C₂₆H₂₉N₃O₅+0.5H₂O: C, 66.09; H, 6.40; N, 8.89; Found: C, 65.96; H,6.33; N, 9.07.

5.123-[4-(4-IMIDAZOL-1-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer-supported triphenylphosphine (1.6 mmol/g, 10 g, 16 mmol)was added to a stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (2.49 g, 8.52mmol) in THF (100 mL) at 0° C., followed by diisopropyldiazene-1,2-dicarboxylate (3.36 ml, 17.04 mmol). After stirring for 30minutes, (4-(chloromethyl)phenyl)methanol (2.00 g, 12.78 mmol) wasadded. The mixture was stirred for one hour then filtered. The resin waswashed with methanol (3×30 mL) and methylene chloride (3×30 mL). Thecombined filtrate was evaporated in vacuo to give an oil, which waspurified on silica gel column (MeOH/CH₂Cl₂ gradient from 1% to 5% in 30min) to give4-carbamoyl-4-[4-(4-chloromethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as an oil (3.38 g, 92% yield): ¹H NMR (DMSO-d₆) δ1.97-2.35 (m, 4H, CH₂CH₂), 3.50 (s, 3H, CH₃), 4.35-4.62 (m, 2H, CH₂),4.73 (dd, J=4.8, 10.3 Hz, 1H, NCH), 4.78 (s, 2H, CH₂), 5.26 (s, 2H,CH₂), 7.19 (d, 1H, NHH), 7.25-7.35 (m, 2H, Ar), 7.41-7.54 (m, 5H, Ar),7.58 (d, J=0.4 Hz, 1H, NHH).

Step 2: Imidazole (0.19 g, 2.84 mmol), and diisopropylethylamine (0.24mL, 1.42 mmol) were added to a stirred solution of4-carbamoyl-4-[4-(4-chloromethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.61 g, 1.42 mmol) in acetonitrile (15 mL). Themixture was heated at 70° C. overnight. To the mixture was, addedpotassium carbonate (0.20 g, 1.48 mmol), and the mixture was heated at80° C. for three hours. The mixture was concentrated and then purifiedon silica gel column (MeOH/CH₂Cl₂ from 1% to 10% in 30 minutes) to give3-[4-(4-Imidazol-1-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (0.12 g, 37% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 18/2 in 10 min(acetonitrile/0.1% H₃PO₄), 2.50 min (96.8%); mp: 248-250° C.; ¹H NMR(DMSO-d₆) δ 1.88-2.07 (m, 1H, CHH), 2.36-2.47 (m, 1H, CHH), 2.53-2.63(m, 1H, CHH), 2.82-2.99 (m, 1H, CHH), 4.17-4.47 (m, 2H, CH₂), 5.10 (dd,J=5.2, 13.3 Hz, 1H, NCH), 6.92 (s, 1H, Ar), 7.20 (t, J=1.2 Hz, 1H, Ar),7.24-7.37 (m, 4H, Ar), 7.42-7.54 (m, 3H, Ar), 7.78 (s, 1H, Ar), 10.96(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.35, 31.20, 45.08, 49.20, 51.58,69.19, 114.95, 115.27, 119.56, 127.58, 128.07, 128.54, 129.81, 129.97,133.31, 136.14, 137.35, 137.59, 153.40, 167.99, 170.96, 172.83; LCMSMH=431; Anal. Calcd for C₂₄H₂₂N₄O₄+0.5H₂O: C, 65.59; H, 5.28; N, 12.75;Found: C, 65.43; H, 5.15; N, 12.64.

5.133-{4-[4-(1,1-DIOXO-1-THIOMORPHOLIN-4-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: A slurry of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidtert-butyl ester (1.5 g, 4.49 mmol), N,N-diisopropylethylamine (784 μl,4.49 mmol), and K₂CO₃ (620 mg, 4.49 mmol) in DMF (15 mL) was stirred for5 minutes at room temperature, followed by addition of(4-chloromethyl-phenyl)-methanol (902 mg, 4.49 mmol). The mixture wasstirred at room temperature for about 15 hours then heated to 70° C. for3 hours. Piperidine (800 μl) was added to the mixture to scavengeunconsumed (4-chloromethyl-phenyl)-methanol. The mixture was stirred foran additional 18 hours at 70° C. The mixture was diluted with water (50mL) and EtOAc (200 mL). The pH of the aqueous was adjusted to about 4using 1 N HCl, and the phases were split in a separatory funnel. Theaqueous layer was saturated with NaCl and extracted with additionalEtOAc (200 mL). The organic layers were combined, washed with brine,dried (Na₂SO₄), and concentrated on rotovap to give 3.5 g of a tan oil.A portion of this oil (2.1 g) was purified on a SiO₂ flash column(CombiFlash, 80 g SiO₂ prepacked column, MeOH/dichloromethane gradient)to give4-carbamoyl-2-[4-(4-hydroxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid tert-butyl ester as a white foam (1.1 g, 90% yield, based onportion purified): ¹H NMR (DMSO-d₆) δ 1.39 (s, 9H, tBu), 2.00-2.13 (m,3H, CHH, CH₂), 2.13-2.31 (m, 1H, CHH), 4.41 (s, 2H, CH₂), 4.50 (d, J=5.7Hz, 2H, CH₂), 4.69 (dd, J=4.6, 10.3 Hz, 1H, CH), 5.19 (t, J=5.7 Hz, 1H,OH), 5.24 (s, 2H, CH₂), 6.75 (br. s., 1H, NH), 7.22 (br. s., 1H, NH),7.25-7.37 (m, 4H, Ar), 7.42-7.53 (m, 3H, Ar); ¹³C NMR (DMSO-d₆) δ 24.69,27.56, 31.50, 44.78, 54.08, 62.60, 69.45, 81.42, 114.97, 115.18, 126.52,127.57, 129.71, 130.03, 133.27, 134.86, 142.40, 153.42, 168.12, 169.85,172.94; LCMS MH=455.

Step 2: To a solution of4-carbamoyl-2-[4-(4-hydroxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid tert-butyl ester (250 mg, 0.55 mmol) in dichloromethane (5 mL),cooled in an ice bath to 0° C., was added N,N-diisopropylethylamine (115μl, 0.66 mmol) followed by methanesulfonyl chloride (47 μl, 0.605 mmol).After 5 minutes, the mixture was allowed to warm up to room temperature.The mixture was stirred for about 45 minuites at room temperature, thenmore MsCl (20 μl) was added. The reaction was complete after 10 minutesas judged by LCMS. The crude mixture was concentrated and the residuewas dried further in vacuum oven at 40° C. overnight to give the crudeproduct as a white solid (320 mg). LCMS indicated that the obtainedsolid contained about 5: 1 mixture of4-carbamoyl-2-[4-(4-methanesulfonyloxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid tert-butyl ester and4-carbamoyl-2-[4-(4-chloromethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid tert-butyl ester (MH=533 and 473, respectively). The mixture wasused in the next step without further purification. To a solution of thecrude product (293 mg, 0.55 mmol, assuming quantitative yield fromprevious step) and N,N-diisopropylethylamine (240 μl, 1.375 mmol) inacetonitrile (5 mL), was added thiomorpholine 1,1-dioxide (82 mg, 0.605mmol). The mixture was stirred at room temperature for about 45 minutesand then more thiomorpholine 1,1-dioxide (82 mg, 0.605 mmol) was added.After 3 hours, the mixture was heated to reflux for about 4 hours andthen stirred at room temperature for 2 days. The volatiles were removedin vacuo and the residue was partitioned between EtOAc (150 mL) and 1 NNaHCO₃ (30 mL). The aqueous layer was washed with additional EtOAc (150mL). The organic layers were combined, washed with brine, dried(Na₂SO₄), and concentrated on a rotovap to give4-carbamoyl-2-{4-[4-(1,1-dioxo-1-thiomorpholin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid tert-butyl ester as an off-white solid (340 mg). LCMS MH=572. Thesolid was used in the next step without further purification.

Step 3: To a stirred solution of4-carbamoyl-2-{4-[4-(1,1-dioxo-1-thiomorpholin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid tert-butyl ester (230 mg, 0.40 mmol) in THF (10 mL), was added a 1Msolution of KOtBu (402 μl, 0.402 mmol). The resulting mixture wasstirred at room temperature for about 2 hours, then more KOtBu (100 μl)was added. After approximately another 2.5 hours, the reaction mixturewas cooled in an ice bath and then transferred to a 1 N aqueous HClsolution. The mixture was concentrated to dryness and the residue wasredissolved in minimal DMF and 1 N HCl (1: 1) and filtered. The filtratecontaining the crude product was purified by injection onto a C-18preparatory HPLC column. The product was eluted with anacetonitrile/water gradient (0.1% formic acid in both mobile phases) andfractions were collected by mass trigger. The desired fractions werecombined and concentrated in vacuo to give3-{4-[4-(1,1-Dioxo-1-thiomorpholin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydroisoindol-2-yl}-piperidine-2,6-dione as a white solid (113 mg, 56%yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm,20/80 acetonitrile/0.1% H₃PO₄, 4.91 min (97.5%); mp: 156-158° C.; ¹H NMR(DMSO-d₆) δ 1.89-2.04 (m, 1H, CHH), 2.35-2.48 (m, 1H, CHH), 2.52-2.64(m, 1H, CHH), 2.74-3.01 (m, 5H, 2CH₂, CHH), 3.03-3.16 (m, 4H, 2CH₂),3.68 (s, 2H, CH₂), 4.25 (d, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.4 Hz, 1H,CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.23 (s, 2H, CH₂), 7.25-7.40(m, 4H, Ar), 7.42-7.56 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆)δ 21.24, 30.06, 43.97, 48.93, 49.12, 50.46, 58.16, 68.23, 113.87,114.13, 126.60, 127.76, 128.70, 128.83, 132.18, 134.44, 136.40, 152.36,166.87, 169.84, 171.71; LCMS MH=498; Anal Calcd for C₂₅H₂₇N₃O₆S: C,60.35; H, 5.47; N, 8.44; S, 6.44; Found: C, 55.59; H, 5.24; N, 7.92; S,5.96.

5.144-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYL}-PIPERIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER

Step 1: To the THF solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.45 g, 1.5 mmol), was added triphenyl phosphine resin(1.75 g, 1.6 mmol/g loading, 2.86 mmol) and DIAD (0.55 mL, 2.86 mmol) at0° C. After being stirred at 0° C. for 10 minutes4-(4-hydroxymethyl-benzyl)-piperidine-1-carboxylic acid tert-butyl esterwas added to the mixture, and the resulting mixture was stirred at roomtemperature overnight. The mixture was filtered and the filtrate wasconcentrated and extracted with EtOAc (30 mL) and Na₂CO₃ (20 mL). Theorganic layer was washed with water (20 mL) and brine (20 mL), andconcentrated. The resulting oil was purified on silica gel column togive4-{4-[2-(1-carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperidine-1-carboxylicacid tert-butyl ester as an oil (0.85 g, 90%).

Step 2: To the THF solution (20 mL) of4-{4-[2-(1-carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperidine-1-carboxylicacid tert-butyl ester (0.85 g, 1.5 mmol), was added potassium t-butoxide(0.16 g, 1.5 mmol) at 0° C. The mixture was stirred for 15 minutes at 0°C. and quenched with 5 mL of 1N HCl solution followed by 15 mL ofsaturated NaHCO₃ solution. The mixture was extracted with EtOAc (20 mL).The organic layer was concentrated in vacuo. The resulting oil waspurified on silica gel column eluted with CH₂Cl₂ and methanol to give4-{4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperidine-1-carboxylicacid tert-butyl ester as a oil (660 mg, 80%). mp: 180-182° C. HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradientacetonitrile/0.1% H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at100/0 for 5 min: t_(R)=7.69 min (98%). ¹H NMR (DMSO-d₆) δ 0.92-1.12 (m,2H, CH₂), 1.16-1.24 (m, 1H, CHH), 1.38 (s, 9H, CH₃, CH₃, CH₃), 1.46-1.58(m, 2H, CH₂), 1.59-1.74 (m, 1H, CH), 1.89-2.06 (m, 1H, CHH), 2.35-2.47(m, 1H, CHH), 2.56-2.71 (m, 4H, CH₂, CHH, CHH), 2.79-3.01 (m, 1H, CHH),3.79-4.00 (m, 2H, CH₂), 4.18-4.51 (m, 2H, CH₂), 5.01-5.16 (m, 1H, NCH),5.20 (s, 2H, CH₂), 7.20 (d, J=8.1 Hz, 2H, Ar), 7.28-7.36 (m, 2H, Ar),7.32-7.32 (m, 1H, Ar), 7.40 (d, J=8.1 Hz, 2H, Ar), 7.43-7.56 (t, J=8.3Hz, 1H, Ar), 10.91-11.07 (m, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.29, 28.01,31.13, 31.39, 37.18, 41.74, 45.02, 51.51, 69.40, 78.31, 114.90, 115.13,127.64, 129.06, 129.74, 129.89, 133.24, 134.00, 139.87, 153.46, 153.74,167.94, 170.91, 172.76; LCMS MH=548. Anal Calcd for C₃₁H₃₇N₃O₆+0.8H₂O:C, 66.25; H, 6.92; N, 7.48; Found: C, 66.09; H, 6.83; N, 7.67.

5.153-[1-OXO-4-(4-PIPERIDIN-4-YLMETHYL-BENZYLOXY)-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONEHYDROGEN CHLORIDE

To the CH₂Cl₂ solution (10 mL) of4-{4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperidine-1-carboxylicacid tert-butyl ester (0.5 g, 1.0 mmol), was added hydrogen chloride inether solution (2.0 M, 5 mL, 10 mmol). The mixture was stirred at roomtemperature overnight. The mixture was filtered. The resulting solid wasstirred with ether to give3-[l-oxo-4-(4-piperidin-4-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dionehydrogen chloride as white solid (194 mg, 50%). mp: 200-202° C. HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradientacetonitrile/0.1% H3PO4 in H2O from 5/95 to 100/0 in 5 min and stayed at100/0 for 5 min: tR=4.90 min (96%). 1H NMR (DMSO-d6) δ 1.35 (d, J=11.9Hz, 2H, CH2), 1.62-1.73 (m, 2H, CH2), 1.74-1.87 (m, 1H, CH), 1.91-2.05(m, 1H, CHH), 2.33-2.48 (m, 1H, CHH), 2.52-2.64 (m, 3H, CH2, CHH), 2.77(d, J=10.8 Hz, 2H, CH2), 2.84-3.01 (m, 1H, CHH), 3.21 (d, J=12.1 Hz, 2H,CH2), 4.11-4.51 (m, 2H, CH2), 5.12 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.21(s, 2H, CH2), 7.21 (d, J=8.1 Hz, 2H, Ar), 7.28-7.37 (m, 2H, Ar), 7.42(d, J=8.1 Hz, 2H, Ar), 7.45-7.54 (m, 1H, Ar), 8.50-8.75 (m, 1H, HCl),8.80-9.02 (m, 1H, HCl), 10.97 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.31,28.04, 31.14, 34.82, 41.23, 42.89, 45.01, 51.51, 69.34, 114.93, 115.16,127.71, 129.09, 129.76, 129.87, 133.24, 134.25, 139.25, 153.43, 167.92,170.91, 172.78; LCMS MH=448. Anal Calcd for C26H29N3O4HCl+1.1H2O: C,61.98; H, 6.44; N, 8.34; Cl, 7.04; Found: C, 61.96; H, 6.63; N, 8.00;Cl, 7.06.

5.163-(4-((5-(MORPHOLINOMETHYL)BENZOFURAN-2-YL)METHYOXY)-1-OXOSIOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Hexamethylenetetramine (14.0 g, 100 mmol) was added in oneportion under N₂ to a stirred solution of 4-hydroxybenzaldehyde (12.2 g,100 mmol) in trifluoroacetic acid (100 mL). After addition, the mixturewas heated in oil bath at 90° C. for 24 hours. The reaction was quenchedwith 140 mL of 3N HCl and cooled to room temperature over 1 hour. Themixture was extracted with CH₂Cl₂ (4×100 mL) and combined CH₂Cl₂solution was concentrated. Ethanol (15 mL) was added to the residue at40° C. and then cooled in an ice bath for 30 minutes. The mixture wasfiltered and solid was washed with cold ethanol (10 mL) to give5-formylsalicylaldehyde (5.0 g, 33% yield): ¹H NMR (DMSO-d₆) δ 7.16 (d,J=8.4 Hz, 1H), 8,00-8,04 (dd, J=2.4 and 8.7 Hz, 1H), 8.21 (d, J=2.4 Hz,1H), 9.89 (s, 1H), 10.34 (s, 1H), 11.79 (s, 1H).

Step 2: A mixture of 5-formylsalicylaldehyde (3.9 g, 26.0 mmol), ethylbromoacetate (4.4 g, 26.0 mmol), potassium carbonate (5.4 g, 39.0 mmol)and molecular sieve (3.9 g) in DMF (40 mL) was heated at 85° C. oil bathfor 2 hours then at 120° C. for 5 hours. The reaction mixture was cooledto room temperature and diluted with EtOAc (100 mL). The mixture wasfiltered and solid was washed EtOAc (50 mL). Filtrate was washed withwater (3×50 mL) and brine (50 mL), and dried. The solvent was removedand the residue was stirred with ether (20 mL) and hexane (20 mL) togive ethyl 5-formylbenzofuran-2-carboxylate (3.3 g, 59% yield): ¹H NMR(DMSO-d₆) δ1.35 (t, J=7.2 Hz, 3H), 4.35-4.42 (q, J=6.9 Hz, 2H),7.92-7.95 (m, 2H), 8.03-8.07 (dd, J=1.5 and 8.7 Hz, 1H), 8.42 (b, 1H),10.10 (s, 1H).

Step 3: Morpholine (1.2 g, 13.8 mmol) was added to a stirred solution ofethyl 5-formylbenzofuran-2-carboxylate (1.5 g, 6.9 mmol) in methanol (60mL). Molecular sieve (4 A, 1.5 g) was added, followed by acetic acid(0.4 g, 6.9 mmol) and sodium cyanoborohydride (0.7 g, 10.3 mmol). Theresulting mixture was stirred at room temperature for 2 hours. Thereaction mixture was filtered and solid was washed with methanol (40mL). Filtrate was concentrated and the residue was dissolved in EtOAc(100 mL). EtOAc solution was washed with sat. NaHCO₃ (30 mL) and brine(30 mL), and dried (K₂CO₃). The solvent was removed and the residue waspurified by chromatography (SiO₂, EtOAc: CH₂Cl₂ 40: 60) to give5-morpholin-4-ylmethyl-benzofuran-2-carboxylic acid ethyl ester (1.2 g,61% yield): ¹H NMR (CDCl₃) δ 1.43 (t, J=6.9 Hz, 3H), 2.45 (t, J=4.5 Hz,4H), 3.58 (s, 2H), 3.71 (t, J=4.5 Hz, 4H), 4.41-4.48 (q, J=6.9 Hz, 2H),7.42-7.45 (dd, J=1.8 and 8.7 Hz, 1H), 7.49 (d, J=0.9 Hz, 1H), 7.52 (d,J=8.4 Hz, 1H), 7.61 (d, J=0.9 Hz, 1H).

Step 4: A solution of LiAlH₄/THF (1M, 8 mL, 8.0 mmol) in THF (10 mL) wascooled in an ice bath to 5° C. A solution of5-morpholin-4-ylmethyl-benzofuran-2-carboxylic acid ethyl ester (1.8 g,6.2 mmol) in THF (20 mL) was added dropwise at 5-10° C. After addition,the mixture was stirred in an ice bath for 30 minutes. The reactionmixture was carefully quenched with sat. Na₂CO₃ (50 mL) in an ice bathand mixture was diluted with CH₂Cl₂ (50 mL). The aq. layer was extractedCH₂Cl₂ (3×40 mL) and combined CH₂Cl₂ solution was washed with sat.NaHCO₃ (40 mL) and brine (40 mL) and dried. The solvent was removed andthe residue was purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 5: 95)to give (5-morpholin-4-ylmethyl-benzofuran-2-yl)-methanol (1.3 g, 86%yield): ¹H NMR (CDCl₃) δ 2.45 (t, J=4.5 Hz, 4H), 2.70 (b, 1H), 3.55 (s,2H), 3.71 (t, J=4.8 Hz, 4H), 4.74 (s, 2H), 6.59 (s, 1H), 7.20-7.24 (dd,J=1.5 and 8.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H).

Step 5: Diisopropyl azodicarboxylate (0.8 g, 4.1 mmol) was added slowlyto a stirred suspension of triphenylphosphine-polymer bound (3.5 g, 4.4mmol) in THF (40 mL) at 3-5° C. After stirred at 3° C. for 10 minutes, asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol) and 5-morpholin-4-ylmethyl-benzofuran-2-yl)-methanol (0.9 g, 3.6mmol) in THF (60 mL) was added slowly at 3-6° C. After stirred at 3° C.for 5 minutes, mixture was stirred at room temperature overnight. Thereaction mixture was filtered and solid was washed with CH₂Cl₂ (40 mL).Filtrate was concentrated and the residue was dissolved in CH₂Cl₂ (100mL) and washed with sat NaHCO₃ (40 mL), water (2×30 mL) and brine (30mL), and dried (K₂CO₃). The solvent was removed and the residue waspurified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 5: 95) to give methyl5-amino-4-(4-((5-morpholinomethyl)benzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.9 g, 64% yield): ¹H NMR (CDCl₃) 2.13-2.47 (m, 8H), 3.57 (s, 2H), 3.63(s, 3H), 3.70-3.72 (m, 4H), 4.35 (d, J=17.7 Hz, 1H), 4.44 (d, J=17.7 Hz,1H), 4.86-4.91 (d, J=5.7 and 8.7 Hz, 1H), 5.24 (s, 2H), 5.36 (b, 1H),6.30 (b, 1H), 6.77 (s, 1H), 7.17-7.19 (dd, J=1.8 and 6.9 Hz, 1H),7.28-7.31 (dd. J=1.5 and 8.4 Hz, 1H), 7.41-7.48 (m, 3H), 7.52 (d, J=1.2Hz, 1H).

Step 6: A solution of potassium t-butoxide/THF (1M, 1.9 mL, 1.9 mmol)was added slowly to a stirred solution of methyl5-amino-4-(4-((5-morpholinomethyl)benzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.9 g, 1.7 mmol) in THF (25 mL) at 5° C. The reaction mixture wasstirred at 5° C. for 1 h then quenched with sat. NH₄Cl (5 mL). Themixture was stirred with CH₂Cl₂ (50 mL) and water (15 mL). The aqueouslayer was extracted with CH₂Cl₂ (30 mL), and combined CH₂Cl₂ solutionwas washed with brine (30 mL) and dried (K₂CO₃). The solvent was removedand the residue was purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂5:95) to give3-(4-((5-morpholinomethyl)benzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.2 g, 25% yield): mp 233-235° C.; ¹H NMR (DMSO-d₆) δ 1.95-2.09 (m,1H), 2.35-2.59 (m, 6H), 2.89-2.92 (m, 1H), 3.54-3.57 (m, 6H), 4.25 (d,J=15 Hz, 1H), 4.36 (d, J=18 Hz, 1H), 5.07-5.13 (dd, J=6 and 12 Hz, 1H),5.42 (s, 2H), 7.08 (s, 1H), 7.27-7.57 (m, 6H), 10.96 (s, 1H); ¹³C NMR(DMSO-d₆) δ 22.28, 31.16, 45.03, 51.56, 53.06, 62.32, 62.52, 66.15,107.05, 110.80, 115.14, 115.66, 121.61, 126.00, 127.48, 129.81, 129.95,132.58, 133.41, 152.80, 152.95, 153.82, 167.88, 170.93, 172.79; Calcdfor C₂₇H₂₇N₃O₆+1.0H₂O: C, 63.90; H, 5.76; N, 8.28; Found: C, 63.97; H,5.40; N, 8.20.

5.17 3-(4-(4-(((2S,6R)-2,6-DIMETHYLMORPHOLINO)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: In a 250-mL RB flask, L-glutamine c-tert-butyl ester (7.83 g,32.8 mmol) and N,N-diisopropylethylamine (11.46 ml, 65.6 mmol) wereslurried in acetonitrile (100 mL) at room temperature. The suspensionwas stirred for about 10 minutes and then a solution of methyl2-(bromomethyl)-3-(tert-butyldimethylsilyloxy)benzoate (11.4 g, 29.8mmol) in acetonitrile (20 mL) was added dropwise over about 10 minutes.The reaction mixture was heated in an oil bath to a slow reflux (80° C.)for 4 hours. The reaction mixture was allowed to cool to roomtemperature for about 1 hour and then a solution of cesium fluoride(4.53 g, 29.8 mmol) in water (15 mL) was added. The resulting mixturewas vigorously stirred at room temperature for about 1 hour at whichpoint LCMS indicated desilylation was complete. The reaction mixture wasdiluted with acetonitrile and filtered to remove undissolved solids. Thesolids were washed with additional acetonitrile. The filtrate and washes(total volume 200 mL) were diluted further with EtOAc (300 mL),transferred to a 1-L separatory funnel, and washed with 0.5N AqueousKH₂PO₄ (100 mL, pH ˜5). To the aqueous layer was added 1 N HCl inportions (˜20 mL, pH changed from pH 7-8 to pH ˜5 using pH paper). NaCl(˜10 g) and EtOAc (˜200 mL) were added to aqueous layer. The mixture wasshaken vigorously in a separatory funnel. The organic layers werecombined, washed with brine (50 mL), dried (Na₂SO₄), and concentrated onrotovap to give 15 g of an off-white solid. This solid containing thecrude product was slurried in acetonitrile (200 mL) and the suspensionwas heated in an oil bath to reflux (85° C.) for 30 minutes withstirring. The mixture was allowed to cool down to room temperature over1 hour then aged at 4° C. for another 2 hours. The solid formed wascollected by suction filtration. The remaining solid in the flask wastransferred onto a filter funnel using some MTBE. The cake was washedwith additional MTBE (total filtrate volume ˜300 mL), suction dried, andthen placed in a vacuum oven at 40° C. for several hours to affordtert-butyl 5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate asa white solid (7.3 g 72% yield, adjusted for purity of starting materialand product): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240nm, 30/70 acetonitrile/0.1% H₃PO₄, 2.91 min (96.9%); mp: 198-200° C.; ¹HNMR (DMSO-d₆) δ 1.39 (s, 9H, tBu), 1.93-2.14 (m, 3H, CH₂, CHH),2.15-2.33 (m, 1H, CHH), 4.35 (s, 2H, CH₂), 4.61-4.83 (m, 1H, CH), 6.76(br. s., 1H, NH), 6.97-7.07 (m, 1H, Ar), 7.11-7.20 (m, 1H, Ar), 7.26(br. s., 1H, NH), 7.29-7.36 (m, 1H, Ar), 10.10 (s, 1H, OH); ¹³C NMR(DMSO-d₆) δ 24.81, 27.56, 31.44, 44.71, 54.02, 81.38, 113.72, 117.96,127.99, 129.36, 133.36, 152.50, 168.36, 169.88, 172.94; LCMS MH=335;Anal Calcd for C₁₇H₂₂N₂O₅+0.19H₂O: C, 60.45; H, 6.68; N, 8.29; Found: C,60.44; H, 6.62; N, 8.27.

Step 2: In a 250-mL RB flask, tert-butyl5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (3 g, 8.79mmol) and triphenyl phosphine on polystyrene (1.6 mmol/g resin, 10.99 g,17.59 mmol) were slurried in THF (100 mL, 1220 mmol) at roomtemperature. The resin was allowed to swell with gentle stirring for 5minutes then the mixture was cooled in an ice bath at 0° C. To themixture, DIAD (3.42 mL, 17.59 mmol) was added using a syringe in a rapiddropwise fashion. After 10 minutes, (4-(chloromethyl)phenyl)methanol(2.066 g, 13.19 mmol) was added as a solid in one portion. The ice bathwas removed and the mixture was stirred at room temperature for 6 hours.The resin was suction filtered and rinsed on filter funnel withsuccessive washes of dichloromethane and MeOH (2×, ˜50 mL each wash).The combined filtrates and washes were concentrated in vacuo to a syrupwhich was partitioned between EtOAc (˜300 mL) and water (˜100 mL). Theorganic layer was washed with brine, dried (Na₂SO₄), and concentrated invacuo to give the crude product as a tan oil (˜10 g). The oil waspurified on a SiO₂ flash column (CombiFlash, 330 g SiO₂ prepackedcolumn, 0% to 5% MeOH in dichloromethane gradient) to give tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas a white foam which was crushed to a fine powder (3.6 g, 87% yield);¹H NMR (DMSO-d₆) δ 1.39 (s, 9H, tBu), 2.00-2.14 (m, 3H, CHH, CH₂),2.14-2.35 (m, 1H, CHH), 4.43 (s, 2H, CH₂), 4.70 (dd, J=4.7, 10.4 Hz, 1H,CH), 4.78 (s, 2H, CH₂), 5.27 (s, 2H, CH₂), 6.66-6.83 (m, 1H, NH),7.18-7.28 (m, 1H, NH), 7.29 (d, J=2.3 Hz, 1H, Ar), 7.32 (d, J=2.6 Hz,1H, Ar), 7.40-7.58 (m, 5H, Ar); ¹³C NMR (DMSO-d₆) δ 24.69, 27.56, 31.50,44.78, 45.83, 54.08, 69.13, 81.41, 114.91, 115.26, 127.92, 129.00,129.73, 130.03, 133.31, 136.78, 137.38, 153.35, 168.09, 169.85, 172.93.

Step 3: To a solution of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(250 mg, 0.529 mmol) in acetonitrile (10 mL), was added(2S,6R)-2,6-dimethylmorpholine (183 mg, 1.586 mmol) and DIEA (0.138 ml,0.793 mmol). The resulting mixture was stirred at 60° C. for 3 hours.The reaction mixture was concentrated in vacuo and further dried in avacuum oven to give tert-butyl5-amino-2-(4-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas a clear glassy solid (360 mg). LCMS MH=552. The solid was used in thenext step without further purification

Step 4: tert-Butyl5-amino-2-(4-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.528 mmol, assume theoretical yield from previous step) was taken upin dry THF (5 mL). To the stirred solution at room temperature, wasadded KOtBu (0.581 ml, 0.581 mmol, 1.0 M in THF) dropwise. The resultingmixture (pale yellow clear solution) was stirred for 1 hour at roomtemperature. Another 1.1 eq of KOtBu was added (0.581 ml, 0.581 mmol,1.0 M THF) and the mixture was stirred for another 1 hour (LCMSindicated reaction was complete). The reaction mixture was cooled on iceand then transferred portionwise to a flask with 2 M formic acid in MeCN(50 mL). The crude reaction mixture was concentrated in vacuo to give anoily residue which was dissolved in minimal water/DMF mixture (˜2 mL/8mL) and filtered, and the filtrate containing the crude product waspurified by injection onto a C-18 preparatory HPLC column. The productwas eluted with an acetonitrile/water gradient (0.1% formic acid in bothmobile phases, 5 to 30% MeCN over 12 minutes) and fractions werecollected by mass trigger. The desired fractions were combined andconcentrated in vacuo to give3-(4-(4-(((2S,6R)-2,6-dimethylmorpholino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (55 mg, 22% yield over step 3 and step 4): HPLC: WatersSymmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 5% grad 95% in 10 min,acetonitrile/0.1% H₃PO₄, 5.84 min (95.6%); mp: 164-166° C.; ¹H NMR(DMSO-d₆) δ 1.00 (s, 3H, CH₃), 1.02 (s, 3H, CH₃), 1.52-1.74 (m, 2H, CHH,CHH), 1.88-2.12 (m, 1H, CHH), 2.32-2.47 (m, 1H, CHH), 2.53-2.62 (m, 1H,CHH), 2.62-2.71 (m, 2H, CHH, CHH), 2.83-3.03 (m, 1H, CHH), 3.44 (s, 2H,CH₂N), 3.48-3.63 (m, 2H, 2×CH), 4.25 (d, J=17.4 Hz, 1H, CHH), 4.42 (d,J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.23 (s, 2H, CH₂O), 7.20-7.39 (m, 4H, Ar), 7.39-7.59 (m, 3H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 18.93, 22.33, 31.18, 45.06, 51.55, 58.89, 61.66,69.39, 70.94, 114.96, 115.22, 127.63, 128.95, 129.80, 129.92, 133.30,135.25, 137.69, 153.49, 167.99, 170.96, 172.81; LCMS MH=478; Anal Calcdfor C₂₇H₃₁N₃O₅+0.34H₂O: C, 67.05; H, 6.60; N, 8.69; H₂O, 1.27; Found: C,67.20; H, 6.63; N, 8.52; H₂O, 1.27.

5.183-(1-OXO-4-((5-(PIPERIDIN-1-YL)BENZOFURAN-2-YL)METHOXY)ISOINDOLIN-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of ethyl 5-nitrobenzofuran-2-carboxylate (5.0 g, 21.2mmol) and 10% Pd/C (0.5 g) in EtOAc (300 mL) was hydrogenated at 50 psiovernight. The reaction mixture was filtered through celite and washedwith EtOAc (100 mL). Filtrate was concentrated and the residue waspurified by chromatography (SiO₂, EtOAc: Hexane 4: 6) to give ethyl5-aminobenzofuran-2-carboxylate (4.5 g, 100% yield): ¹H NMR (CDCl₃) δ1.41 (t, J=7.2 Hz, 3H), 3.68 (b, 2H), 4.38-4.45 (q, J=7.2 Hz, 2H),6.80-6.84 (dd, J=2.4 and 9.0 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 7.35-7.36(d, J=3.3 Hz, 1H), 7.38 (s, 1H).

Step 2: N,N-Diisopropylethylamine (3.8 g, 29.2 mmol) was added to astirred solution of ethyl 5-aminobenzofuran-2-carboxylate (2.5 g, 12.2mmol) and 1,5-dibromopentane (5.0 g, 21.9 mmol) in toluene (40 mL). Theresulting mixture was heated at 110° C. oil bath overnight. The reactionmixture was cooled to room temperature and filtered and solid was washedwith toluene (25 mL). Filtrate was concentrated and the residue waspurified by chromatography (SiO₂, EtOAc: Hexane 1: 9) to give ethyl5-piperidin-1-yl-benzofuran-2-carboxylate (3.0 g, 89%); ¹H NMR (CDCl₃) δ1.42 (t, J=6.2 Hz, 3H), 1.53-1.61 (m, 2H), 1.71-1.79 (m, 4H), 3.09-3.13(t, J=5.4 Hz, 4H), 4.39-4.46 (q, J=6.9 Hz, 2H), 7.09-7.10 (d, J=2.4 Hz,1H), 7.15-7.19 (dd, J=2.7 and 9.3 Hz, 1H), 7.42-7.46 (m, 2H).

Step 3: A solution of LiAlH₄/THF (1M, 11 mL, 11 mmol) in THF (10 mL) wascooled to 3° C. A solution of ethyl5-piperidin-1-yl-benzofuran-2-carboxylate (2.9 g, 10.7 mmol) in THF (30mL) was added slowly at 3-10° C. The reaction mixture was stirred at 3°C. for 30 minutes then quenched with sat. Na₂CO₃ (50 mL). The mixturewas stirred with CH₂Cl₂ (50 mL) and aqueous layer was extracted withCH₂Cl₂ (3×40 mL). Combined CH₂Cl₂ solution was washed with sat. NaHCO₃(40 mL) and brine (40 mL), and dried. The solvent was removed and theresidue was purified by chromatography (SiO₂, EtOAc: CH₂Cl₂ 3: 7) togive (5-piperidin-1-yl-benzofuran-2-yl)-methanol (2.4 g, 95% yield): ¹HNMR (CDCl₃) δ 1.23-1.27 (m, 2H), 1.54-1.60 (m, 4H), 2.82 (b, 1H), 3.07(t, J=6.0 Hz, 4H), 4.68 (s, 2H), 6.45 (s, 1H), 6.95-7.00 (m, 2H), 7.29(d, J=9.0 Hz, 1H); ¹³C NMR (CDCl₃) δ 24.20, 26.14, 53.10, 58.11, 104.20,108.83, 111.19, 117.01, 128.53, 149.07, 150.30, 156.94.

Step 4: Diisopropyl azodicarboxylate (0.8 g, 4.1 mmol) was added slowlyto a stirred suspension of triphenylphosphine-polymer bound (3.5 g, 4.4mmol) in THF (40 mL) at 3-6° C. After stirred at 3° C. for 10 minutes, asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol) and (5-piperidin-1-yl-benzofuran-2-yl)-methanol (0.8 g, 3.6 mmol)in THF (60 mL) was added slowly at 3-6° C. After stirred at 3° C. for 10minutes, mixture was stirred at room temperature overnight. The reactionmixture was filtered and solid was washed with CH₂Cl₂ (30 mL). Filtratewas concentrated and the residue was dissolved in CH₂Cl₂ (80 mL) andwashed with sat. NaHCO₃ (40 mL), water (2×35 mL) and brine (35 mL), anddried. The solvent was removed and the residue was purified bychromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-5-oxo-4-(1-oxo-4-((5-piperidin-1-yl)benzofuran-2-yl)methoxy)isoindolin-2-yl)pentanoate(0.7 g, 51% yield): ¹H NMR (CDCl₃) δ 1.55-1.59 (m, 2H), 1.72-1.77 (m,4H), 2.31-2.39 (m, 4H), 3.08-3.11 (m, 4H), 4.40 (d, J=18 Hz, 1H), 4.44(d, J=18 Hz, 1H), 4.87-4.92 (dd, J=6.0 and 9.0 Hz, 1H), 5.21 (s, 2H),5.49 (s, 1H), 6.38 (s, 1H), 6.71 (s, 1H), 7.02-7.18 (m, 3H), 7.36-7.46(m, 2H). Step 5: A solution of potassium t-butoxide/THF (1M, 1.5 mL, 1.5mmol) was added slowly to a stirred solution of methyl5-amino-5-oxo-4-(1-oxo-4-((5-piperidin-1-yl)benzofuran-2-yl)methoxy)isoindolin-2-yl)pentanoate(0.6 g, 1.2 mmol) in THF (20 mL) at 5° C. and stirred for 30 minutesthen quenched with sat. NH₄Cl (5 mL). The mixture was stirred withCH₂Cl₂ (50 mL) and water (15 mL). The aqueous layer was extracted withCH₂Cl₂ (30 mL) and combined CH₂C₂ solution was washed with water (30 mL)and dried. The solvent was removed and the residue was purified bychromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give3-(1-oxo-4-((5-(piperidin-1-yl)benzofuran-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione(0.3 g, 43% yield): mp 242-244° C.; ¹H NMR (DMSO-d₆) δ 1.09 (m, 2H),1.50-1.64 (m, 4H), 1.90-2.02 (m, 2H), 2.49-2.51 (m, 2H), 2.80-2.95 (m,1H), 3.03-3.07 (m, 4H), 4.25 (d, J=17.7 Hz, 1H), 4.35 (d, J=17.4 Hz,1H), 5.05-5.15 (m, 1H), 5.37 (s, 2H), 6.97-7.09 (m, 3H), 7.35-7.51 (m,4H), 10.96 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.28, 23.78, 25.53, 31.16,45.04, 51.51, 62.61, 107.29, 107.71, 111.12, 115.15, 116.69, 127.96,129.78, 129.95, 133.40, 148.89, 149.23, 152.57, 152.99, 167.88, 170.93,172.70; Calcd for C₂₇H₂₇N₃O₅+0.2H₂O: C, 67.97; H, 5.79; N, 8.81; Found:C, 67.88; H, 5.75; N, 8.62.

5.194-AMINO-1-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYL}-PYRIDINIUMFORMATE

Pyridin-4-amine (0.82 g, 8.70 mmol) was added to a stirred solution ofmethyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.75 g, 1.74 mmol) in DMF (15 ml) at 50° C. for three hours. To themixture was added potassium carbonate (0.24 g, 1.74 mmol), and themixture was heated at 75° C. for five hours. The mixture was purified bypreparative HPLC to give4-amino-1-{4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyridiniumformate as a brown solid (0.20 g, 26% yield); HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in5 min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H3PO4): 5.00 min(99.1%); mp: 300-302° C.; 1H NMR (DMSO-d6) δ 1.92-2.05 (m, 1H, CHH),2.35-2.47 (m, 1H, CHH), 2.54-2.64 (m, 1H, CHH), 2.83-3.00 (m, 1H, CHH),4.19-4.47 (m, 2H, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.26 (s, 2H,NH2 or CH2), 5.36 (s, 2H, CH2 or NH2), 6.86 (d, J=7.4 Hz, 2H, CH2),7.27-7.58 (m, 7H, Ar), 8.22-8.43 (m, 4H, Ar), 11.00 (br. s., 1H, NH);13C NMR (DMSO-d6) δ 22.35, 31.15, 45.09, 51.58, 59.39, 69.00, 109.56,115.00, 115.36, 128.12, 128.32, 129.85, 129.94, 133.29, 135.35, 137.21,142.93, 153.31, 158.57, 158.67, 168.02, 170.89, 172.80; LCMS M+=457;Anal. Calcd for C26H25N4O4 HCOO: C, 64.53; H, 5.22; N, 11.15; Found: C,56.18; H, 5.07; N, 10.01.

5.203-(1-OXO-4-((5-PIPERIDIN-1-YLMETHYL)BENZOFURAN-2-YL)METHOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Piperidine (1.2 g, 14.1 mmol) was added to a stirred solution ofethyl 5-formylbenzofuran-2-carboxylate (1.5 g, 6.9 mmol) in methanol (60mL). Molecular sieve (1.5 g) was added, followed by acetic acid (0.4 g,6.9 mmol) and sodium cyanoborohydride (0.7 g, 10.3 mmol). The resultingmixture was stirred at room temperature for 3 hours. The mixture wasfiltered and solid was washed with methanol (40 mL). Filtrate wasconcentrated and the residue was dissolved in EtOAc (100 mL) and washedwith sat. NaHCO₃ (35 mL) and brine (35 mL), and dried (K₂CO₃). Thesolvent was removed and the residue was purified by chromatography(SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give5-piperidin-1-ylmethyl-benzofuran-2-carboxylic acid ethyl ester (1.0 g,49% yield): ¹H NMR (CDCl₃) δ 1.40-1.48 (m, 3H), 1.57-1.64 (m, 4H), 2.44(b, 1H), 3.60 (s, 2H), 3.97-3.98 (m, 2H), 4.40-4.47 (q, 2H), 7.40-7.63(m, 4H).

Step 2: A solution of 5-piperidin-1-ylmethyl-benzofuran-2-carboxylicacid ethyl ester (1.0 g, 3.4 mmol) in THF (15 mL was added slowly to astirred solution of LiAlH₄/THF (1M, 4.4 mL, 4.4 mmol) in THF (10 mL) at5-8° C. After addition, the mixture was stirred at 5° C. for 30 minutesthen quenched with sat. Na₂CO₃ (50 mL). The mixture was stirred withCH₂Cl₂ (50 mL) and aqueous layer was extracted with CH₂Cl₂ (2×30 mL).Combined CH₂Cl₂ solution was washed with sat. NaHCO₃ (30 mL) and brine(30 mL), and dried. The solvent was removed and the residue was purifiedby chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give(5-piperidin-1-ylmethyl-benzofuran-2-yl)-methanol (0.5 g, 63% yield): ¹HNMR (CDCl₃) δ 1.45-1.46 (m, 2H), 1.55-1.62 (m, 4H), 2.40 (s, 4H), 3.46(s, 1H), 3.52 (s, 2H), 4.71 (s, 2H), 6.55 (s, 1H), 7.20 (d, J=8.4 Hz,1H), 7.26 (d, J=8.4 Hz, 1H), 7.45 (s, 1H).

Step 3: Diisopropyl azodicarboxylate (0.6 g, 3.1 mmol) was added slowlyto a stirred suspension of triphenylphosphine-polymer bound (2.5 g, 3.1mmol) in THF (40 mL) at 3-5° C. After stirred at 3° C. for 10 minutes, asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.6 g, 2.0mmol) and (5-piperidin-1-ylmethyl-benzofuran-2-yl)-methanol (0.5 g, 2.0mmol) in THF (40 mL) was added slowly at 3-6° C. The reaction mixturewas stirred at 3° C. for 5 minutes then warmed to room temperatureovernight. The reaction mixture was filtered and solid was washed withCH₂Cl₂ (40 mL). Filtrate was concentrated and the residue was dissolvedin CH₂Cl₂ (100 mL) and washed with sat. NaHCO₃ (30 mL), water (30 mL)and brine (30 mL), and dried. The solvent was removed and the residuewas purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to givemethyl5-amino-5-oxo-4-(1-oxo-4-((5-(piperidin-1-ylmethyl)benzofuran-2-yl)methoxy)isoindolin-2-yl)pentanoate(0.6 g, 56% yield): ¹H NMR (CDCl₃) δ 1.42-1.46 (m, 2H), 1.53-1.60 (m,4H), 2.12-2.45 (m, 8H), 3.55 (s, 2H), 3.62 (s, 3H), 4.40 (d, J=17.7 Hz,1H), 4.44 (d, J=17.7 Hz, 1H), 4.87-4.92 (dd, J=5.7 and 8.7 Hz, 1H), 5.23(s, 2H), 5.47 (s, 1H), 6.40 (s, 1H), 6.77 (s, 1H), 7.15-7.18 (dd, J=2.1and 6.6 Hz, 1H), 7.26-7.32 (m, 1H), 7.40-7.51 (m, 4H).

Step 4: A mixture of methyl5-amino-5-oxo-4-(1-oxo-4-((5-piperidin-1-ylmethyl)benzofuran-2-yl)methoxy)isoindolin-2-yl)pentanoate(0.6 g, 1.1 mmol) and K₂CO₃ (0.2 g, 1.1 mmol) in DMF (10 mL) was heatedat 80° C. oil bath for 3 hours. The reaction mixture was concentratedand the residue was stirred with water (10 mL) and EtOAc (10 mL). Solidwas collected and reslurried in acetone (10 mL) and hexane (10 mL) togive3-(1-oxo-4-((5-piperidin-1-ylmethyl)benzofuran-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione(0.2 g, 50% yield): mp 202-204° C.; ¹H NMR (DMSO-d₆) δ 1.46-1.47 (m,6H), 1.96-2.00 (m, 1H), 2.31-2.58 (m, 6H), 2.84-2.96 (m, 1H), 3.48 (s,2H), 4.25 (d, J=17.4 Hz, 1H), 4.35 (d, J=17.4 Hz, 1H), 5.06-5.13 (dd,J=5.1 and 13.2 Hz, 1H), 5.41 (s, 2H), 7.07 (s, 1H), 7.23-7.27 (dd, J=1.5and 8.4 Hz, 1H), 7.34-7.37 (dd, J=0.9 and 6.9 Hz, 1H), 7.46-7.53 (m,4H), 10.96 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.25, 23.98, 25.50, 31.16,45.03, 51.55, 53.74, 62.55, 62.70, 107.05, 110.68, 115.13, 115.65,121.39, 125.89, 127.42, 129.81, 129.94, 133.41, 152.72, 152.97, 153.74,167.88, 170.93, 172.79; Calcd for C₂₈H₂₉N₃O₅: C, 68.98; H, 6.00; N,8.62; Found: C, 68.67; H, 6.03; N, 8.53.

5.21 TERT-BUTYL4-(4-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YLOXY)METHYL)PHENYL)PIPERIDINE-1-CARBOXYLATE

Step 1: BH₃THF (2.88 ml, 2.88 mmol, 1.0 M in THF) was added dropwise toa solution of 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (800mg, 2.62 mmol) in THF (10 ml) at 0° C. After 15 minutes, the ice bathwas removed and the clear solution was allowed to stir overnight (˜17hours). The reaction mixture was cooled in an ice bath and quenched withH₂O (25 mL). EtOAc (100 mL) was added and the mixture was washed with 1N NaHCO₃ (˜40 mL) and brine, dried (Na₂SO₄), and concentrated in vacuo.The oily residue was dissolved in dichloromethane and concentrated againand then dried in a vacuum oven at 40° C. to give tert-butyl4-(4-(hydroxymethyl)phenyl)piperidine-1-carboxylate as a clear oil (707mg, 93% yield). The oil solidified upon standing and was used in thenext step without further purification. LCMS MH=292, 218; ¹H NMR(CHLOROFORM-d) δ 1.48 (s, 9H, tBu), 1.56-1.72 (m, 3H, CHH, CHH, OH),1.75-1.89 (m, 2H, CHH, CHH), 2.53-2.71 (m, 1H, CH), 2.73-2.92 (m, 2H,CHH, CHH), 4.17-4.32 (m, 2H, CHH, CHH), 4.67 (d, J=5.9 Hz, 2H, CH₂),7.21 (d, J=8.1 Hz, 2H, Ar), 7.32 (d, J=8.3 Hz, 2H, Ar); ¹³C NMR(CHLOROFORM-d) δ 28.50, 33.22, 42.49, 65.21, 77.22, 79.47, 127.02,127.34, 138.96, 145.40. Carbamate carbon signal is not observed.

Step 2: To a solution of tert-butyl5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.7 g, 1.96mmol) in THF (25 ml), was added triphenyl phosphine on polystyrene (1.6μm/mmol, 1.845 g, 2.95 mmol). The resin was allowed to swell for severalminutes at room temperature, and then the reaction mixture was cooled inan ice bath at 0° C. DIAD (0.574 ml, 2.95 mmol) was added dropwise whilestirring. After about 15 minutes, tert-butyl4-(4-(hydroxymethyl)phenyl)piperidine-1-carboxylate (0.70 g, 2.40 mmol)was added as a solution in dry THF (5 mL). After about 10 minutes, theice bath was removed and the resulting mixture was stirred at roomtemperature for 48 hours. The reaction mixture was filtered with suctionand the resin was washed successively with dichloromethane then MeOH (3×swell/shrink cycles). After the final MeOH wash, the combined filtratewas concentrated in vacuo. The oily residue was partitioned betweenEtOAc (˜200 mL) and Na₂CO₃ (sat. ˜70 mL). The EtOAc layer was washedwith brine, dried (Na₂SO₄), and concentrated in vacuo to give a foamwhich was stored in a vacuum oven at 40° C. overnight to affordtert-butyl4-(4-((2-(5-amino-1-tert-butoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)phenyl)piperidine-1-carboxylate)(1.9 g, assume theoretical yield). The foam obtained was used in thenext step without further purification.

Step 3: KOtBu (0.722 mL, 0.722 mmol, 1.0 M in THF) was added dropwise toa solution of tert-butyl4-(4-((2-(5-amino-1-tert-butoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)phenyl)piperidine-1-carboxylate(400 mg, 0.408 mmol) in dry THF (5 mL) at room temperature. More KOtBu(0.722 mL, 0.722 mmol) was added to reaction mixture after 2.5 hours andstirring was continued at room temperature. After about 20 minutes, themixture transferred to a chilled 0.5N aq. HCl (˜50 mL). EtOAc (250 mL)was added and the mixture transferred to a separatory funnel. The EtOAclayer was washed with brine, dried (Na₂SO₄), and concentrated in vacuoand the residue was dried further in a vacuum oven to give 380 mg of atan oil. The crude product was dissolved in minimal DMF (˜10 mL) andpurified by injection onto a C-18 preparatory HPLC column. The productwas eluted with an acetonitrile/water gradient (0.1% formic acid in bothmobile phases, 30 to 80% MeCN over 20 minutes) and fractions werecollected by mass trigger. The desired fractions were combined andconcentrated in vacuo to give tert-butyl4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)phenyl)piperidine-1-carboxylateas a white solid (84 mg, 39% yield for step 2 and step 3): HPLC: WatersSymmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 60/40acetonitrile/0.1% H₃PO₄, 4.76 min (98.7%); mp: 214-216° C.; ¹H NMR(DMSO-d₆) δ 1.29-1.44 (m, 9H, tBu), 1.44-1.58 (m, 2H, 2×CHH), 1.72 (br.s., 2H, CHH, CHH), 1.87-2.08 (m, 1H, CHH), 2.35-2.48 (m, 1H, CHH),2.52-2.99 (m, 5H, 5×CHH), 3.89-4.14 (m, 2H, 2×CHH), 4.24 (d, J=17.6 Hz,1H, CHH), 4.40 (d, J=17.4 Hz, 1H, CHH), 5.10 (dd, J=5.1, 13.2 Hz, 1H,CH), 5.20 (s, 2H, CH₂), 7.18-7.37 (m, 4H, Ar), 7.37-7.55 (m, 3H, Ar),10.96 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 28.07, 31.18, 32.66,41.35, 43.89, 45.06, 51.55, 69.35, 78.53, 114.90, 115.16, 126.81,127.95, 129.78, 129.92, 133.28, 134.39, 145.62, 153.48, 153.86, 167.99,170.97, 172.84; LCMS MH=534; Anal Calcd for C₃₀H₃₅N₃O₆+1.5H₂O: C, 64.27;H, 6.83; N, 7.49; Found: C, 64.22; H, 6.72; N, 7.36.

5.22 3-(1-OXO-4-(4-(PIPERIDIN-4-YL)BENZYLOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE HYDROGEN CHLORIDE

A 2 N HCl (10 mL, 20.00 mmol) in Et₂O was added to tert-butyl4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)phenyl)piperidine-1-carboxylate(54 mg, 0.101 mmol). The reaction flask was sonicated to loosen solidadhering on side of flask and the resulting suspension was sealed andstirred at room temperature. After about 4 hours, LCMS indicatedreaction was complete. The reaction mixture was diluted with additionalEt₂O and then filtered through a fritted funnel with suction. Theremaining solid in reaction flask was transferred to funnel and washedwith additional Et₂O. The cake was dried in vacuum oven at 40° C. toafford3-(1-oxo-4-(4-(piperidin-4-yl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dionehydrochloride as a fluffy off-white solid hydrochloride salt (47 mg, 99%yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm,20/80 acetonitrile/0.1% H3PO4, 3.62 min (96.0%); mp: 280-282° C.; 1H NMR(DMSO-d6) E 1.67-2.12 (m, 5H, 5×CHH), 2.32-2.48 (m, 1H, CHH), 2.52-2.64(m, 1H, CHH), 2.76-3.08 (m, 4H, 4×CHH), 3.26-3.46 (m, 2H, 2×CHH), 4.24(d, J=17.6 Hz, 1H, CHH), 4.41 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.1,13.2 Hz, 1H, CH), 5.22 (s, 2H, C H₂O), 7.26 (d, J=8.1 Hz, 2H, Ar), 7.33(d, J=7.7 Hz, 2H, Ar), 7.40-7.54 (m, 3H, Ar), 8.48-9.01 (m, 2H, 2×NH),10.96 (s, 1H, NH); 13C NMR (DMSO-d6) □ 22.34, 29.30, 31.18, 43.48,45.03, 51.55, 69.28, 114.94, 115.22, 126.61, 128.08, 129.80, 129.92,133.28, 134.86, 144.42, 153.45, 167.97, 170.96, 172.81. 1 carbon signalis not observed due to overlap with DMSO-d6; LCMS MH=434; Anal Calcd forC₂₅H₂₇N₃O₄+2 HCl+1.7H₂O: C, 55.91; H, 6.08; N, 7.82; Found: C, 55.84; H,5.82; N, 7.70.

5.233-{4-[4-(3-MORPHOLIN-4-YL-PROPYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: (Triphenylphosphoranylidene)acetaldehyde (500 mg, 1.64 mmol) wasadded to the stirred solution of methyl 4-formylbenzoate (2.0 g, 12.18mmol) in tetrahydrofuran (50 mL). The reaction mixture was heated atreflux for two hours before (triphenylphosphoranylidene)acetaldehyde(500 mg, 1.64 mmol) was added to the reaction mixture. The reactionmixture was kept at reflux for 21 hours and then (triphenylphosphoranylidene)acetaldehyde (3.5 g, 11.45 mmol) was added to thereaction mixture which was kept at reflux for 8 hours. The reactionmixture was diluted by EtOAc (80 mL) and then washed by NH₄Cl (Sat. 40mL), water (40 mL) and brine (40 mL) respectively. The organic layer wasdried by MgSO₄ and concentrated to give dark solid. The dark solid wassuspended in diethyl ether (50 mL) and filtered through celite and thesolid was washed by diethyl ether (50 mL×3). The filtrate wasconcentrated and purified by silica chromatography to give4-(3-Oxo-propenyl)-benzoic acid methyl ester as an off white solid (1.04g, 33% yield); LCMS MH=191; ¹H NMR (DMSO-d₆) δ 3.88 (s, 3H, CH₃), 6.97(dd, J=7.6, 16.0 Hz, 1H, CH), 7.82 (d, J=16.1-Hz, 1H, CH), 7.90 (d,J=8.5 Hz, 2H, Ar), 8.02 (d, J=8.3 Hz, 2H, Ar), 9.72 (d, J=7.6 Hz, 1H,CHO).

Step 2: Morpholine (0.715 ml, 8.20 mmol) was added to the stirredsolution of (E)-methyl 4-(3-oxoprop-1-enyl)benzoate (520 mg, 2.73 mmol).The clear solution was added by molecular sieves (2.2 g) and acetic acid(0.157 ml, 2.73 mmol). Thirty minutes later, sodium cyanoborohydride(258 mg, 4.10 mmol) was added to above yellow reaction suspension. Thereaction was complete in 15 minutes at room temperature. The reactionmixture combined with another batch of reaction started with (E)-methyl4-(3-oxoprop-1-enyl)benzoate) (512 mg) was added by water (2 mL) andstirred for 10 minutes before it was filtered through celite. Thefiltrate was concentrated and purified by ISCO chromatography to give4-(3-Morpholin-4-yl-propenyl)-benzoic acid methyl ester as yellow liquid(550 mg, 39% yield); LCMS MH=262.

Step 3: Palladium on carbon (120 mg, 0.056 mmol) was added to thestirred solution of (E)-methyl 4-(3-morpholinoprop-1-enyl)benzoate (710mg, 2.72 mmol) in MeOH (20 mL). The reaction flask was sealed andvacuumed. The reaction charged with H₂ (1 atm) was stirred at roomtemperature and the reaction was complete in 1 hour. The reactionmixture combined with another batch of reaction started with (E)-methyl4-(3-morpholinoprop-1-enyl)benzoate (50 mg) was filtered through celite.And the solid was washed by MeOH (20 mL×3). The filtrate wasconcentrated and was purified by ISCO chromatography to give4-(3-Morpholin-4-yl-propyl)-benzoic acid methyl ester as clear solid(690 mg, 90% yield) and the compound was put to next step withoutfurther purification; LCMS MH=264.

Step 4: LiAlH₄ (1.3 mL, 2.62 mmol) in THF (2 M) solution was added tothe stirred solution of methyl 4-(3-morpholinopropyl)benzoate (690 mg,2.62 mmol) in tetrahydrofuran (25 mL) under −78° C. drop wise. Thereaction mixture was stirred under −78° C. for 30 minutes and thenallowed to 0° C. slowly. Two hours later, the reaction mixture wascooled down to −78° C. and 1.3 mL LiAlH₄ (2M in THF) was added to thereaction mixture. And the cold bath was removed after addition and thereaction mixture was stirred at room temperature for 1 hour and thereaction was complete. To the reaction mixture, NaOH (0.6 mL, 10 N) andwater (0.4 mL) were added. The resulting suspension was stirred at roomtemperature for 20 minutes before it was filtered through celite. Thesolid was washed by EtOAc (40 mL×4) and concentrated under vacuo to give[4-(3-morpholin-4-yl-propyl)-phenyl]-methanol as a clear oil (600 mg,97% crude yield) which was used without further purification; LCMSMH=236.

Step 5: Polymer bonded PPh₃ (727 mg, 2.77 mmol, 1.6 mmol/g) was added tothe stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (450 mg,1.540 mmol) in THF (17 mL) at 0° C. The reaction mixture was stirred at0° C. for 20 minutes before DIAD (0.539 ml, 2.77 mmol) was added dropwise. The resulting reaction mixture was stirred for 20 minutes, and(4-(3-morpholinopropyl)phenyl)methanol (471 mg, 2.001 mmol) in THF (3mL) was added to the mixture. Thirty minutes later, the ice bath wasremoved and the reaction mixture was stirred at room temperature for 2hours before the reaction stopped progressing. The reaction mixturecombined with another batch of reaction started with methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (100 mg) wasfiltered and washed with dichloromethane (25 mL×6). The filtrate wasconcentrated and purified by ISCO chromatography to give4-Carbamoyl-4-{4-[4-(3-morpholin-4-yl-propyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as glass like solid (450 mg, 47% yield); LCMS MH=510;¹H NMR (DMSO-d₆) δ 1.72 (quin, J=7.5 Hz, 2H, CH₂), 2.00-2.21 (m, 2H,CHH, CHH), 2.21-2.40 (m, 8H, CH₂, CH₂, CH₂, CH₂), 2.60 (t, J=7.6 Hz, 2H,CH₂), 3.50 (s, 3H, CH₃), 3.52-3.62 (m, 4H, CH₂, CH₂), 4.31-4.45 (m, 1H,CHH), 4.45-4.61 (m, 1H, CHH), 4.72 (dd, J=4.7, 10.2 Hz, 1H, CHH), 5.20(s, 2H, CH₂), 7.11-7.32 (m, 5H, Ar, NH), 7.35-7.49 (m, 3H, Ar), 7.58 (s,1H, NH).

Step 6: To the stirred solution of methyl5-amino-4-(4-(4-(3-morpholinopropyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(400 mg, 0.785 mmol) in tetrahydrofuran (18 mL) at 0° C., was addedpotassium 2-methylpropan-2-olate (88 mg, 0.785 mmol). The mixture wasstirred at 0° C. for 1.5 hours and the reaction was complete. The coldreaction mixture was diluted by EtOAc (30 mL), followed by the additionof HCl (aq, 1N, 1 mL), NaHCO₃ (sat. 0.6 mL) and brine (3 mL). Themixture was extracted and organic layer was washed by brine (5 mL). Theorganic layer was combined with the organic layer from anther batch ofreaction mixture started with methyl5-amino-4-(4-(4-(3-morpholinopropyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(50 mg). The mixture was dried by MgSO₄ and concentrated to give solid(460 mg). The solid was triturated in ether (15 mL) to give3-{4-[4-(3-Morpholin-4-yl-propyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (165 mg, 41% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80, (acetonitrile/0.1% H₃PO₄),4.0 min (97%); mp: 190-192° C.; ¹H NMR (DMSO-d₆) δ 1.71 (quin, J=7.5 Hz,2H, CH₂), 1.91-2.04 (m, 1H, CHH), 2.21-2.36 (m, 6H, M₀₁), 2.39-2.47 (m,1H, CHH), 2.59 (t, J=7.6 Hz, 3H, CHH, CH₂), 2.81-3.00 (m, 1H, CHH),3.50-3.62 (m, 4H, CH₂, CH₂), 4.19-4.30 (m, 1H, CHH), 4.33-4.48 (m, 1H,CHH), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CHH), 5.20 (s, 2H, CH₂), 7.23 (d,J=7.9 Hz, 2H, Ar), 7.32 (d, J=7.7 Hz, 2H, Ar), 7.39 (d, J=7.9 Hz, 2H,Ar), 7.43-7.55 (m, 1H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.33, 27.72, 31.16, 32.53, 45.07, 51.56, 53.28, 57.52, 66.17, 69.45,114.97, 115.16, 127.79, 128.39, 129.77, 129.93, 133.27, 133.87, 141.92,153.49, 168.00, 170.95, 172.81; LCMS MH=478; Anal. Calcd forC₂₇H₃₁N₃O₅+1 H₂O+0.26 Ether: C, 65.42; H, 6.97; N, 8.16; Found: C,65.41; H, 6.77; N, 8.19.

5.243-(1-OXO-4-((6-PIPERIDIN-1-YLMETHYL)BENZOFURAN-2-YL)METHOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-hydroxy-4-methylbenzaldehyde (4.6 g, 33.9 mmol),ethyl 2-bromoacetate (5.7 g, 33.9 mmol), K₂CO₃ (7.0 g, 50.9 mmol) andmolecular sieve (4.6 g) in DMF (40 mL) was heated at 85° C. for 2 hoursthen at 120° C. for 5 hours. The reaction mixture was cooled and dilutedwith EtOAc (100 mL). The mixture was filtered, and filtrate was washedwith water (3×50 mL) and brine (50 mL), and dried. The solvent wasremoved and the residue was purified by chromatography (SiO₂,EtOAc:Hexane=1:9) to give ethyl 6-methylbenzofuran-2-carboxylate (3.1 g,44% yield): ¹H NMR (DMSO-d₆) δ 1.34 (t, J=7.2 Hz, 3H), 4.32-4.39 (q,J=6.9 Hz, 2H), 7.35-7.58 (m, 2H), 7.66-7.70 (m, 2H).

Step 2: N-Bromosuccinimide (5.6 g, 31.5 mmol) was added to a stirredsolution of ethyl 6-methylbenzofuran-2-carboxylate (3.1 g, 15.0 mmol) inCCl₄ (50 mL). The resulting mixture was heated at 70° C. oil bath with a300 W bulb shining for 5 hours. The reaction mixture was cooled andfiltered. Filtrate was concentrated and the residue was purified bychromatography (SiO₂, EtOAC: Hexane=1:9) to give ethyl6-(bromomethyl)benzofuran-2-carboxylate (2.8 g, 66% yield): ¹H NMR(DMSO-d₆) δ 1.34 (t, J=7.2 Hz, 3H), 4.38 (q, J=7.2 Hz, 2H), 4.86 (s,2H), 7.40-7.45 (m, 1H), 7.76-7.84 (m, 3H).

Step 3: A mixture of piperidine (1.0 g, 11.3 mmol), K₂CO₃ (3.6 g, 26mmol) and 18-crown-6 (catalytic amount) in acetone (10 mL) was heated at60° C. oil bath. A solution of ethyl6-(bromomethyl)benzofuran-2-carboxylate (2.0 g, 7.1 mmol) in acetone (10mL) was added dropwise and the mixture was stirred at 60° C. oil bathfor 3 hours. The reaction mixture was cooled and filtered. Filtrate wasconcentrated and the residue was dissolved in EtOAc (100 mL) and washedwith water (2×35 mL) and brine (35 mL), and dried. The solvent wasremoved and the residue was purified by chromatography (SiO₂, CH₃OH:CH₂Cl₂ 3: 97) to give ethyl6-(piperidin-1-ylmethyl)benzofuran-2-carboxylate (1.5 g, 73% yield): ¹HNMR (CDCl₃) δ 1.40-1.46 (m, 5H), 1.53-1.61 (m, 4H), 2.37-2.40 (m, 4H),3.59 (s, 2H), 4.40-4.47 (q, J=6.9 Hz, 2H), 7.26-7.30 (m, 1H), 7.49 (d,J=0.9 Hz, 1H), 7.56-7.60 (m, 2H).

Step 4: A solution of ethyl6-(piperidin-1-ylmethyl)benzofuran-2-carboxylate (1.5 g, 5.2 mmol) inTHF (20 mL) was added slowly to a stirred solution of LiAlH₄/THF (1M,6.7 mL, 6.7 mmol) in THF (10 mL) at 3-8° C. After addition, the mixturewas stirred at 3° C. for 30 minutes then quenched with sat. Na₂CO₃ (50mL). The mixture was diluted with CH₂Cl₂ (50 mL) and aqueous layer wasextracted with CH₂Cl₂ (3×40 mL). Combined CH₂Cl₂ solution was washedwith brine (35 mL) and dried. The solvent was removed and the residuewas purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give[6-(piperidin-1-ylmethyl)benzofuran-2-yl]methanol (0.9 g, 68% yield): ¹HNMR (CDCl₃) δ 1.41-1.46 (m, 2H), 1.54-1.61 (m, 4H), 2.39 (m, 4H), 3.56(s, 2H), 4.72 (s, 2H), 6.60 (s, 1H), 7.14-7.17 (dd, J=1.2 and 7.8 Hz,1H), 7.42-7.47 (m, 2H); ¹³C NMR (CDCl₃) δ 24.34, 25.83, 54.42, 57.92,63.95, 103.88, 111.95, 120.36, 124.36, 127.09, 135.02, 155.38, 156.71.

Step 5: Diisopropyl azodicarboxylate (0.8 g, 4.0 mmol) was added to astirred suspension of triphenylphosphine-polymer bound (3.4 g, 4.3 mmol)in THF (40 mL) at 3-6° C. After stirred at 3° C. for 10 minutes, asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol) and [6-(piperidin-1-ylmethyl)benzofuran-2-yl]methanol (0.9 g, 3.5mmol) in THF (60 mL) was added slowly at 3-6° C. After stirred at 3° C.for 5 minutes, the mixture was stirred at room temperature overnight.The reaction mixture was filtered and solid was washed with CH₂Cl₂ (30mL). Filtrate was concentrated and the residue was dissolved in CH₂Cl₂(100 mL) and washed with sat. NaHCO₃ (40 mL), water (40 mL), brine (40mL) and dried. The solvent was removed and the residue was purified bychromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-5-oxo-4-(1-oxo-4-((6-piperidin-1-ylmethyl)benzofuran-2-yl)methoxy)isoindolin-2-yl)pentanoate(0.9 g, 64%).

Step 6: A mixture of methyl5-amino-5-oxo-4-(1-oxo-4-((6-piperidin-1-ylmethyl)benzofuran-2-yl)methoxy)isoindolin-2-yl)pentanoate(0.9 g, 1.7 mmol) and K₂CO₃ (0.2 g, 1.7 mmol) in DMF (10 mL) was heatedat 80° C. oil bath for 2.5 hours. The reaction mixture was cooled andconcentrated. Residue was stirred with water (20 mL) and EtOAc (10 mL).Solid was collected and reslurried with hot acetone (10 mL) to give3-(1-oxo-4-((6-piperidin-1-ylmethyl)benzofuran-2-yl)methoxy)isoindolin-2-yl)piperidine-2,6-dione(0.19 g, 22% yield): mp 216-218° C.; ¹H NMR (DMSO-d₆) δ 1.39-1.49 (m,6H), 1.95-1.99 (m, 1H), 2.33-2.58 (m, 6H), 2.86-2.94 (m, 1H), 3.53 (s,2H), 4.25 (d, J=15 Hz, 1H), 4.36 (d, J=18 Hz, 1H), 5.07-5.13 (dd, J=6and 15 Hz, 1H), 5.41 (s, 2H), 7.08 (s, 1H), 7.22 (d, J=9 Hz, 1H), 7.37(d, J=6 Hz, 1H), 7.49-7.59 (m, 4H), 10.96 (s, 1H); ¹³C NMR (DMSO-d₆) δ22.28, 23.92, 25.47, 31.16, 45.04, 51.55, 53.74, 62.52, 62.70, 107.01,111.17, 115.09, 115.63, 120.86, 124.05, 126.34, 129.80, 129.93, 133.41,135.94, 152.41, 152.97, 154.73, 167.88, 170.92, 172.79; Calcd forC₂₈H₂₉N₃O₅+0.8H₂O: C, 67.00; H, 6.14; N, 8.37; Found: C, 66.96, H, 5.96,N, 8.03.

5.25 3-(4-((1-METHYL-1H-BENZO[D]IMIDAZOL-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A mixture of N-methyl 1,2-phenylenediamine (5.4 g, 44.0 mmol)and glycolic acid (5.0 g, 66.0 mmol) in 4N HCl (50 mL) was refluxed for45 minutes then cooled to room temperature. The reaction mixture wasfiltered and filtrate was diluted with water (100 mL). The mixture wascooled in an ice bath with vigorous stirring and neutralized with solidsodium bicarbonate carefully. Solid was collected and recrystallizedfrom 1,4-dioxane (40 mL) to give(1-methyl-1H-benzo[d]imidazol-2-yl)methanol (5.7 g, 80% yield): ¹H NMR(DMSO-d₆) δ 3.82 (s, 3H, N—CH₃), 4.70 (d, J=5.7 Hz, 2H, CH₂O), 5.75 (t,J=5.7 Hz, 1H, OH), 7.14-7.26 (m, 2H, Ar), 7.50-7.57 (m, 2H, Ar); 13C NMR(DMSO-d₆) δ 29.75, 56.39, 109.83, 118.85, 121.28, 122.01, 136.02,141.77, 153.90.

Step 2: Diisopropyl azodicarboxylate (1.0 g, 4.9 mmol) was added to astirred suspension of methyl5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.7 g, 2.5mmol), (1-methyl-1H-benzo[d]imidazol-2-yl)methanol (0.6 g, 3.7 mmol) andtriphenylphosphine-polymer bound (1.6 g, 4.9 mmol) in THF (150 mL) atroom temperature. After addition, mixture was stirred for 2 hours. Thereaction mixture was filtered and solid was washed with methylenechloride (30 mL). Filtrate was concentrated and the residue was purifiedby chromatography (SiO₂, CH₃OH: CH₂C₂ 3: 97) to give methyl5-amino-2-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.7 g, 60%).

Step 3: Potassium t-butoxide/THF (1M, 1.5 mL, 1.5 mmol) was added to astirred solution of methyl5-amino-2-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.7 g, 1.5 mmol) in THF (30 mL) and DMF (10 mL). After addition,mixture was stirred at room temperature for 2 hours. The reactionmixture was cooled in an ice bath and quenched with water (30 mL). Themixture was stirred with methylene chloride (30 mL) and aqueous layerwas extracted with methylene chloride (2×35 mL). Combined organicsolution was washed with water (40 mL) and brine (40 mL), and dried. Thesolvent was removed and the residue was stirred with water (20 mL).Solid was collected and reslurried with ether (10 mL) to give3-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.3 g, 42%) as a white solid: mp 233-235° C.; ¹H NMR (DMSO-d₆) δ1.94-1.99 (m, 1H), 2.39-2.59 (m, 2H), 2.86-2.90 (m, 1H), 3.88 (s, 3H),4.28 (d, J=17.4 Hz, 1H), 4.38 (d, J=17.4 Hz, 1H), 5.06-5.13 (dd, J=5.1and 13.2 Hz, 1H), 5.57 (s, 2H), 7.22 (dt, J=1.1 and 7.3 Hz, 1H), 7.30(dt, J=1.3 and 8.1 Hz, 1H), 7.36 (t, J=4.3 Hz, 1H), 7.53 (d, J=3.8 Hz,2H), 7.58 (d, J=7.7 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 10.96 (s, 1H); ¹³CNMR (DMSO-d₆) δ 22.29, 30.30, 31.13, 44.99, 51.56, 62.87, 110.26,115.17, 115.76, 119.29, 121.78, 122.74, 129.83, 129.95, 133.40, 135.98,141.70, 149.16, 152.91, 167.84, 170.88, 172.79; Calcd. ForC₂₂H₂₀N₄O₄+0.1H₂O: C, 65.05; H, 5.01; N, 13.79; Found: C, 65.01; H,5.08; N, 13.58.

5.264-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-PIPERIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER

Step 1: Polymer-supported triphenylphosphene (1.6 mmol/g, 1.76 g, 2.19mmol) was added to a stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.29 g, 1.01 mmol) in THF (15 mL) at 0° C., followed byaddition of diisopropyl diazene-1,2-dicarboxylate (0.44 ml, 2.19 mmol).After stirring for 30 minutes, 4-hydroxymethyl-piperidine-1-carboxylicacid tert-butyl ester (0.43 g, 2.00 mmol) was added. The mixture wasstirred overnight at room temperature then filtered, washed withmethanol (3×10 mL), then with methylene chloride (3×10 mL). The combinedfiltrate was evaporated in vacuo to give an oil, which was purified onsilica gel column (MeOH/CH₂Cl₂ gradient from 0% to 5% in 60 min) to give4-[2-(l-carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester as a clear oil (0.27 g, 55% yield).

Step 2: Potassium tert-butoxide (0.06 g, 0.55 mmol) was added to astirred solution of4-[2-(1-carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester (0.27 g, 0.55 mmol) in THF (10 mL) at 0° C. for 10minutes. The mixture was quenched with 1N HCl (2 ml) and neutralizedwith saturated sodium bicarbonate (4 ml to pH=8). The mixture was washedwith ethyl acetate (3×20 mL). The combined ethyl acetate phases wereevaporated and then purified on silica gel column (MeOH/CH₂Cl₂ gradientfrom 0% to 5% in 40 min) to give4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester as an off-white solid (0.15 g, 60% yield); HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at50/50 in 10 min (acetonitrile/0.1% H₃PO₄), 3.81 min (96.5%); mp:233-235° C.; ¹H NMR (DMSO-d₆) δ 1.07-1.29 (m, 2H, CH₂), 1.40 (s, 9H,(CH₃)₃), 1.71-1.83 (m, 2H, CH₂), 1.87-2.06 (m, 2H, CHH, CHH), 2.36-2.47(m, 1H, CHH), 2.54-2.64 (m, 1H, CHH), 2.66-2.82 (m, 2H, CH₂), 2.83-3.01(m, 1H, CHH), 3.92-4.07 (m, 4H, CH₂CH₂), 4.17-4.45 (m, 2H, ArCH₂), 5.11(dd, J=5.1, 13.2 Hz, 1H, NCH), 7.23 (d, J=7.9 Hz, 1H, Ar), 7.30 (d,J=7.4 Hz, 1H, Ar), 7.43-7.53 (m, 1H, Ar), 10.97 (s, 0.1H, NH); ¹³C NMR(DMSO-d₆) δ 22.39, 28.09, 28.14, 31.20, 35.28, 43.11 (brs due torotamer), 44.94, 51.55, 71.97, 78.50, 114.51, 114.98, 129.74, 129.84,133.21, 153.73, 153.89, 168.03, 170.99, 172.83; LCMS MH=358; Anal Calcdfor C₂₄H₃₁N₃O₆+0.1H₂O: C, 62.76; H, 6.85; N, 9.15; Found: C, 62.75; H,6.92; N, 8.90.

5.273-[1-OXO-4-(PIPERIDIN-4-YLMETHOXY)-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONEHYDROCHLORIDE

Step 1: Polymer-supported triphenylphosphene (1.6 mmol/g, 1.76 g, 2.19mmol) was added to a stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.29 g, 1.01 mmol) in THF (15 mL) at 0° C., followed byaddition of diisopropyl diazene-1,2-dicarboxylate (0.44 ml, 2.19 mmol).After stirring for 30 minutes, 4-hydroxymethyl-piperidine-1-carboxylicacid tert-butyl ester (0.43 g, 2.00 mmol) was added. The mixture wasstirred overnight at room temperature then filtered, washed withmethanol (3×10 mL), then with methylene chloride (3×10 mL). The combinedfiltrate was evaporated in vacuo to give an oil, which was purified onsilica gel column (MeOH/CH₂Cl₂ gradient from 0% to 5% in 60 min) to give4-[2-(1-carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester as a clear oil (0.27 g, 55% yield).

Step 2: Potassium tert-butoxide (0.060 g, 0.55 mmol) was added to astirred solution of4-[2-(1-carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester (0.27 g, 0.55 mmol) in THF (10 mL) at 0° C. for 10minutes. The mixture was quenched with 1N HCl (2 ml) and neutralizedwith saturated sodium bicarbonate (4 ml to pH=8). The mixture was washedwith ethyl acetate (3×20 mL). The combined ethyl acetate phases wereevaporated and then purified on silica gel column (MeOH/CH₂Cl₂ gradientfrom 0% to 5% in 40 min) to give4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester as an off-white solid (0.15 g, 60% yield); HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at50/50 in 10 min (acetonitrile/0.1% H₃PO₄), 3.81 min (96.5%); mp:233-235° C.; ¹H NMR (DMSO-d₆) δ 1.07-1.29 (m, 2H, CH₂), 1.40 (s, 9H,(CH₃)₃), 1.71-1.83 (m, 2H, CH₂), 1.87-2.06 (m, 2H, CHH, CHH), 2.36-2.47(m, 1H, CHH), 2.54-2.64 (m, 1H, CHH), 2.66-2.82 (m, 2H, CH₂), 2.83-3.01(m, 1H, CHH), 3.92-4.07 (m, 4H, CH₂CH₂), 4.17-4.45 (m, 2H, ArCH₂), 5.11(dd, J=5.1, 13.2 Hz, 1H, NCH), 7.23 (d, J=7.9 Hz, 1H, Ar), 7.30 (d,J=7.4 Hz, 1H, Ar), 7.43-7.53 (m, 1H, Ar), 10.97 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.39, 28.09, 28.14, 31.20, 35.28, 43.11 (brs due torotamer), 44.94, 51.55, 71.97, 78.50, 114.51, 114.98, 129.74, 129.84,133.21, 153.73, 153.89, 168.03, 170.99, 172.83; LCMS MH=358; Anal Calcdfor C₂₄H₃₁N₃O₆+0.1H₂O: C, 62.76; H, 6.85; N, 9.15; Found: C, 62.75; H,6.92; N, 8.90.

Step 3: 2 M HCl/ether (20 mL) was added to a stirred solution of4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester (0.090 g, 0.196 mmol) in dichloromethane (3 mL).The mixture was stirred for three hours and filtered, then dried to give3-[1-oxo-4-(piperidin-4-ylmethoxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dionehydrochloride as a white solid (0.076 g, 98% yield); HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 9/91 in10 min (acetonitrile/0.1% H₃PO₄), 6.22 min (98.0%); mp: 298-300° C.; ¹HNMR (DMSO-d₆) δ 1.43-1.66 (m, 2H, CH₂), 1.83-2.20 (m, 3H, CH₂, CHH),2.32-2.46 (m, 1H, CHH), 2.58 (d, J=16.8 Hz, 1H, CHH), 2.80-3.02 (m, 2H,CH₂), 3.19-3.44 (m, 2H, CH₂), 4.02 (d, J=6.2 Hz, 2H, OCH₂), 4.16-4.48(m, 2H, ArCH₂), 5.13 (dd, J=5.1, 13.2 Hz, 1H, NCH), 7.26 (d, J=8.1 Hz,1H, Ar), 7.32 (d, J=7.4 Hz, 1H, Ar), 7.42-7.55 (m, 1H, Ar), 8.69 (d,J=3.4 Hz, 2H, NH₂Cl), 10.99 (s, 1H, NH); 3C NMR (DMSO-d₆) δ 22.49,25.00, 31.18, 33.00, 42.60, 44.91, 51.55, 71.39, 114.60, 115.13, 129.72,129.88, 133.22, 153.60, 168.01, 171.02, 172.85; LCMS MH=358; Anal Calcdfor C₁₉H₂₄N₃O₄Cl+1.0H₂O: C, 55.41; H, 6.36; N, 10.20; Cl, 8.61; Found:C, 55.72; H, 6.16; N, 9.82; Cl, 8.69.

5.283-[1-OXO-4-(TETRAHYDRO-PYRAN-3-YLMETHOXY)-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer bonded triphenylphosphine (1.6 g, 2.06 mmol, 1.25mmol/g) was added to the stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1, 3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (300 mg, 1.03 mmol) in THF (10 mL) at 0° C. The resultingmixture was stirred at 0° C. for 10 minutes, followed by the addition ofDIAD (412 mg, 2.06 mmol). Fifteen minutes later,(tetrahydro-pyran-3-yl)-methanol (239 mg, 2.06 mmol) was added to themixture. The reaction was stirred at room temperature for 17 hours andthe reaction was complete. The reaction mixture was filtered and thesolid was washed with dichloromethane (6×20 mL). The filtrate wasconcentrated and the residue was purified by ISCO chromatography to give4-carbamoyl-4-[1-oxo-4-(tetrahydro-pyran-3-ylmethoxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a clear oil (256 mg, 64% yield): LCMS MH=391.

Step 2: KOtBu (72 mg, 0.64 mmol) was added to the stirred solution of4-carbamoyl-4-[1-oxo-4-(tetrahydro-pyran-3-ylmethoxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (250 mg, 0.0.64 mmol) in tetrahydrofuran (18 mL) at 0°C. The mixture was stirred at room temperature for 1 hour and thereaction was added by HCl (aq. 0.1N, 6 mL) followed by the addition ofwater (10 mL). The mixture was extracted with dichloromethane (2×20 mL).Organic layers were dried by MgSO₄ and concentrated under vacuo. Theresidue was purified by ISCO chromatography and prep HPLC to give3-[1-oxo-4-(tetrahydro-pyran-3-ylmethoxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (36 mg, 16% yield). HPLC: Waters Symmetry C-18, 3.9 X.150 mm, 5 μm, 1 mL/min, 240 nm, 30/70, (acetonitrile/0.1% H₃PO₄):t_(R)=4.5 (100%); mp: 118-120° C.; ¹H NMR (DMSO-d₆) δ 1.25-1.72 (m, 3H,CH₂, CHH), 1.79-1.92 (m, 1H, CHH), 1.92-2.09 (m, 2H, CH₂), 2.36-2.48 (m,1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.74-3.10 (m, 1H, CHH), 3.66-3.81 (m,1H, CHH), 3.83-4.08 (m, 3H, CH₂, CHH), 4.13-4.47 (m, 2H, CH₂), 5.11 (dd,J=5.0, 13.1 Hz, 1H, NCH), 7.23 (d, J=7.9 Hz, 1H, Ar), 7.31 (d, J=7.0 Hz,1H, Ar), 7.43-7.53 (m, 1H, Ar), 10.97 (s, 1H, NH) * two protons areoverlapped with DMSO's Me peak and it was confirmed by HMQC; ¹³C NMR(DMSO-d₆) δ 22.32, 24.59, 25.42, 31.16, 35.42, 44.90, 51.53, 67.48,69.26, 69.44, 114.45, 115.00, 129.73, 129.81, 133.07, 153.43, 167.98,170.99, 172.83; LCMS MH=359; Anal. Calcd forC₁₉H₂₂N₂O₅+0.57H₂O+0.015CH₂C12+0.04HCOOH: C, 61.56; H, 6.3; N, 7.53;Found: C, 61.16; H, 5.9; N, 7.35.

5.293-(4-((1-METHYL-1H-INDAZOL-3-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Iodomethane (10.9 g, 77.1 mmol) was added slowly to a stirredmixture of 1H-indazole-3-carboxylic acid (5.0 g, 30.8 mmol) andpotassium carbonate (12.8 g, 92.5 mmol) in DMF (30 mL). The resultingmixture was heated at 50° C. oil bath for 4 hours. The reaction mixturewas cooled and poured into ice water (200 mL). The mixture was extractedwith EtOAc (4×50 mL) and the combined EtOAc solution was washed withwater (3×40 mL) and brine (40 mL), and dried (MgSO₄). The solvent wasremoved and the residue was purified by chromatography (SiO₂, EtOAc:Hexane 2:8) to give methyl 1-methyl-1H-indazole-3-carboxylate (3.9 g,66% yield): ¹H NMR (DMSO-d₆) δ 3.93 (s, 3H), 4.17 (s, 3H), 7.33-7.38(ddd, J=1.8, 6.9 and 8.1 Hz, 1H), 7.48-7.53 (ddd, J=1.1, 6.9 and 8.4 Hz,1H), 7.77-7.80 (td, J=0.8 and 8.5 Hz, 1H), 8.06-8.09 (td, J=1.0 and 8.2Hz, 1H); ¹³C NMR (DMSO-d₆) δ 36.26, 51.54, 110.75, 120.99, 122.75,123.10, 126.61, 133.25, 140.64, 162.28.

Step 2: A solution of methyl 1-methyl-1H-indazole-3-carboxylate (3.8 g,20.0 mmol) in ether (100 mL) was cooled to 5° C. A solution of LiBH₄/THF(2M, 15.0 mL, 30 mmol) was added slowly at 5-10° C. The mixture wasstirred at room temperature for 2.5 hours and then cooled in an ice bathand quenched with water (30 mL). The aqueous layer was extracted withCH₂Cl₂ (50 mL) and combined organic solution was washed with water (2×40mL) and brine (40 mL), and dried. The solvent was removed and theresidue was purified by chromatography (SiO₂, EtOAc: Hexane 4: 6) togive (1-methyl-1H-indazol-3-yl)-methanol (2.8 g, 86% yield): ¹H NMR(DMSO-d₆) δ 3.98 (s, 3H), 4.79 (d, J=6.0 Hz, 2H), 5.24 (t, J=6.0 Hz,1H), 7.09-7.14 (dt, J=0.9 and 6.0 Hz, 1H), 7.35-7.40 (dt, J=1.2 and 6.0Hz, 1H), 7.54-7.58 (dt, J=9.0 and 0.6 Hz, 1H), 7.83-7.86 (dt, J=9.0 and0.9 Hz, 1H); ¹³C NMR (DMSO-d₆) δ 34.96, 56.43, 109.39, 119.71, 120.72,121.90, 125.91, 140.58, 144.42.

Step 3: Diisopropyl azodicarboxylate (1.3 g, 6.4 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.9 g, 3.2mmol), (1-methyl-1H-indazol-3-yl)-methanol (0.8 g, 4.8 mmol), andtriphenylphosphine-polymer bound (2.1 g, 6.4 mmol) in THF (60 mL) at5-8° C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and solid was washed withCH₂Cl₂ (30 mL). Filtrate was concentrated and the residue was purifiedby chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-((1-methyl-1H-indazol-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 36%).

Step 4: A solution of potassium t-butoxide/THF (1M, 0.9 mL, 0.9 mmol)was added to a stirred solution of methyl5-amino-4-(4-((1-methyl-1H-indazol-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.4 g, 0.9 mmol) in THF (30 mL) at 5° C. The reaction mixture wasstirred at 5° C. for 5 minutes then warmed to room temperature for 2hours. The reaction mixture was cooled in an ice bath and quenched withsat. NH₄Cl (10 mL). The mixture was diluted with CH₂Cl₂ (50 mL) andwater (20 mL). The aqueous layer was extracted with CH₂Cl₂ (30 mL) andcombined CH₂Cl₂ solution was washed with water (40 mL) and brine (40mL), and dried. The solvent was removed and the residue was purified bychromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give3-(4-((1-methyl-1H-indazol-3-ylmethoxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione(0.2 g, 51% yield): mp 14-142° C.; ¹H NMR (DMSO-d₆) δ 1.93-1.97 (m, 1H),2.38-2.57 (m, 2H), 2.84-2.88 (m, 1H), 4.05 (s, 3H), 4.21 (d, J=17.4 Hz,1H), 4.31 (d, J=17.4 Hz, 1H), 5.04-5.10 (dd, J=4.8 and 13.2 Hz, 1H),5.56 (s, 2H), 7.14-7.19 (dt, J=0.6 and 6.9 Hz, 1H), 7.31-7.34 (dd, J=3.9and 4.8 Hz, 1H), 7.30-7.45 (dt, J=3.9 and 4.8 Hz, 1H), 7.39-7.45 (dt,J=0.9 and 6.6 Hz, 1H), 7.50-7.52 (m, 2H), 7.63 (d, J=8.7 Hz, 1H), 7.83(d, J=7.2 Hz, 1H), 10.93 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.24, 31.15,35.32, 45.08, 51.56, 63.13, 109.88, 115.10, 115.32, 120.06, 120.67,122.15, 126.28, 129.78, 129.90, 133.30, 139.14, 140.58, 153.45, 167.92,170.91, 172.77; Calcd for C₂₂H₂₀N₄O₄: C, 65.34; H, 4.98; N, 13.85;Found: C, 64.96; H, 4.96; N, 13.74.

5.303-(4-((3-METHYLBENZOFURAN-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: Borane/THF (1M, 22.7 mL, 22.7 mmol) was added slowly to astirred solution of 3-methylbenzofuran-2-carboxylic acid (2 g, 11.4mmol) in THF (30 mL) at 5-7° C. After addition, mixture was stirred at5° C. for 10 minutes then warmed to room temperature for 5 hours. Thereaction mixture was cooled in an ice bath and quenched with water (15mL) slowly. The mixture was diluted with CH₂Cl₂ (35 mL) and water (15mL) and aqueous layer was extracted with CH₂Cl₂ (2×35 mL). CombinedCH₂Cl₂ solution was washed with sat. NaHCO₃ (25 mL), water (25 mL) andbrine (25 mL), and dried. The solvent was removed and the residue waspurified by chromatography (SiO₂, CH₂Cl₂) to give(3-methyl-benzofuran-2-yl)-methanol (1.4 g, 78%); ¹H NMR (DMSO-d₆) δ2.21 (s, 3H), 4.56 (d, J=5.7 Hz, 2H), 5.29 (t, J=5.7 Hz, 1H), 7.20-7.31(m, 2H), 7.47-7.56 (m, 2H); ¹³C NMR (DMSO-d₆) δ 7.46, 53.83, 110.71,111.33, 119.48, 122.20, 124.14, 129.51, 152.98, 153.27.

Step 2: Diisopropyl azodicarboxylate (1.3 g, 6.2 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (0.9 g, 3.1mmol), (3-methyl-benzofuran-2-yl)-methanol (0.8 g, 4.6 mmol) andtriphenylphosphine-polymer bound (2.1 g, 6.2 mmol) in THF (60 mL) at5-8° C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and solid was washed withCH₂Cl₂ (30 mL). Filtrate was concentrated and the residue was purifiedby chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-((3-methyl-benzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)-oxopentanoate(1.0 g, 72%).

Step 3: A solution of potassium t-butoxide/THF (1M, 2.2 mL, 2.2 mmol)was added slowly to a stirred solution of methyl5-amino-4-(4-((3-methyl-benzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.0 g, 2.2 mmol) in THF (30 mL) at 5° C. The mixture was stirred at 5°C. for 5 minutes then warmed to room temperature for 2 hours. Thereaction mixture was cooled in an ice bath and quenched with 1N HCl (10mL). The mixture was diluted with CH₂Cl₂ (50 mL) and water (10 mL). Theaqueous layer was extracted with CH₂Cl₂ (30 mL) and combined CH₂Cl₂solution was washed with water (40 mL) and brine (40 mL), and dried. Thesolvent was removed and the residue was purified by chromatography(SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give3-(4-((3-methylbenzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.5 g, 60% yield): mp 210-212° C.; ¹H NMR (DMSO-d₆) δ 1.96-1.98 (m,1H), 2.28 (s, 3H), 2.27-2.57 (m, 2H), 2.83-2.90 (m, 1H), 4.23 (d, J=17.4Hz, 1H), 4.33 (d, J=17.7 Hz, 1H), 5.06-5.12 (dd, J=5.1 and 13.2 Hz, 1H),5.40 (s, 2H), 7.25-7.37 (m, 3H), 7.45-7.48 (dd, J=0.6 and 8.1 Hz, 1H),7.51-7.56 (dt, J=0.9 and 8.1 Hz, 2H), 7.61-7.63 (dd, J-0.9 and 7.8 Hz,1H), 10.94 (s, 1H); ¹³C NMR (DMSO-d₆) δ 7.55, 22.25, 31.16, 45.04,51.54, 60.93, 111.04, 115.23, 115.64, 119.98, 122.60, 125.08, 128.95,129.81, 130.00, 133.38, 147.64, 153.17, 153.68, 167.89, 170.82, 170.91,172.78; Calcd for C₂₃H₂₀N₂O₅: C, 68.31; H, 4.98; N, 6.93; Found: C,68.09; H, 5.00; N, 6.81.

5.313-(1-OXO-4-(PYRIDINE-2-YLMETHOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a mixture of triphenylphosphine polymer supported (0.63 g, 1.88 mmol)and methyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.25 g, 0.86 mmol) in THF (15 mL) cooled down to 0° C., was added dropwise DIAD (0.37 ml, 1.88 mmol). 3-Pyridyl carbinol (0.10 mL, 1.03 mmol)was then added. The reaction mixture was stirred at 0° C. for 1 hour andthen at room temperature overnight. The reaction mixture was thenfiltered through celite. Celite was washed with ethyl acetate (100 mL).The ethyl acetate phase was washed with water, dried with MgSO₄, andsolvent was evaporated. The residue was purified by ISCO flash (40 gcolumn, gradient MeOH/CH₂Cl₂ 0/100 to 5/95 in 30 min, eluting product at5/95). The solvent was evaporated and crude product was carried over tonext step.

To the crude product stirred in THF (10 mL) and cooled down to 0° C.,was added KOtBu (0.064 g, 0.57 mmol) and the reaction mixture wasstirred for 1 hour and 30 minutes. Acetic acid (5 drops) was added toreaction mixture. Ethyl acetate (100 mL) was added and it was washedwith a saturated solution of sodium bicarbonate (2×100 mL) and brine(100 mL), and dried (MgSO₄). After filtration of the drying agent,solvent was concentrated down to give3-(1-oxo-4-(pyridine-2-ylmethoxy)isoindolin-2-yl)piperidine 2,6-dione asa white solid (0.13 g, 43% yield): HPLC: Waters XTerra RPI8, 3.9×150 mm,5 μm, 1 mL/min, 240 nm, 25/75 acetonitrile/0.1% HCOONH4, 3.58 min(98.63%); mp: 235-237° C.; 1H NMR (DMSO-d6) δ 1.86-2.16 (m, 1H, CHH),2.18-2.47 (m, 1H, CHH), 2.53-2.70 (m, 1H, CHH), 2.78-3.06 (m, 1H, CHH),4.16-4.35 (m, 1H, CHH), 4.36-4.52 (m, 1H, CHH), 5.11 (dd, J=5.0, 13.1Hz, 1H, CH), 5.31 (s, 2H, CH2), 7.36 (dd, J=4.3, 7.7 Hz, 2H, Ar),7.41-7.69 (m, 2H, Ar), 7.93 (d, J=7.7 Hz, 1H, Ar), 8.65 (d, J=49.3 Hz,2H, Ar), 10.97 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.33, 31.16, 45.03,51.56, 67.25, 114.97, 115.47, 123.62, 129.83, 130.02, 132.25, 133.36,135.69, 148.94, 149.19, 153.23, 167.93, 170.93, 172.81; LCMS MH=352;Anal. Calcd for C₁₉H₁₇N₃O₄+0.4H₂O: C, 63.64; H, 5.00; N, 11.72; Found:C, 63.34; H, 5.12; N, 11.48.

5.323-(4-((2-METHYLISOINDOLIN-5-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: A solution of LiAlH₄/THF (1M, 24 mL, 24 mmol) was added slowlyto a stirred solution of5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester(3.0 g, 12.0 mmol) in THF (30 mL) at 5° C. After addition, the reactionmixture was warmed slowly to reflux for 2 hours. The reaction mixturewas cooled in an ice bath and quenched with water (20 mL). The mixturewas diluted with EtOAc (25 mL) and filtered through celite. Filtrate wasconcentrated and the residue was dissolved in EtOAc (100 mL). EtOAcsolution was washed with water (2×25 mL) and brine (25 mL), and dried.The solvent was removed to give(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-methanol (1.2 g, 62% yield): ¹HNMR (CDCl₃) δ 2.55 (s, 3H), 3.76 (s, 2H), 3.85 (s, 2H), 4.10 (b, 1H),4.55 (s, 2H), 6.96 (s, 1H), 7.04-7.10 (m, 2H).

Step 2: Diisopropyl azodicarboxylate (0.9 g, 4.6 mmol) was added slowlyto a stirred suspension of triphenylphosphine-polymer bound (3.9 g, 4.9mmol) in THF (40 mL) at 3-5° C. After stirred at 3° C. for 10 minutes, asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.9 g, 3.1mmol) and (2-methyl-2,3-dihydro-1H-isoindol-5-yl)-methanol (0.7 g, 4.0mmol) in THF (60 mL) was added slowly at 3-6° C. The reaction mixturewas stirred at 3° C. for 5 minutes then warmed to room temperature andstirred overnight. The reaction mixture was filtered and solid washedwith CH₂Cl₂ (30 mL). Filtrate was concentrated and the residue wasdissolved in CH₂Cl₂ (100 mL). CH₂Cl₂ solution was washed with sat.NaHCO₃ (40 mL), water (2×30 mL), and brine (30 mL), and dried. Thesolvent was removed and the residue was purified by chromatography(SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-((2-methylisoindolin-5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 39% yield): ¹H NMR (CDCl₃) δ 2.14-2.46 (m, 4H), 2.60 (s, 3H),3.63 (s, 3H), 3.92 (s, 4H), 4.34-4.48 (m, 2H), 4.88-4.92 (dd, J=3.3 and8.7 Hz, 1H), 5.12 (s, 2H), 5.56 (s, 1H), 6.34 (s, 1H), 7.05-7.08 (dd,J=1.5 and 6.9 Hz, 1H), 7.22-7.26 (m, 3H), 7.36-7.44 (m, 2H).

Step 3: A mixture of methyl5-amino-4-(4-((2-methylisoindolin-5-yl)methoxy)-1-oxo-isoindolin-2-yl)-5-oxopentanoate(0.3 g, 0.6 mol) and K₂CO₃ (0.09 g, 0.6 mmol) in DMF (10 mL) was heatedat 80° C. oil bath for 3 hours. The reaction mixture was cooled andconcentrated and the residue was stirred with water (20 mL). Solid wascollected and reslurried with acetone (10 mL) to give3-(4-((2-methylisoindolin-5-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.2 g, 66% yield): mp 262-264° C.; ¹H NMR (DMSO-d₆) δ 1.97-1.99 (m,1H), 2.41-2.59 (m, 5H), 2.91 (m, 1H), 3.80 (s, 4H), 4.27 (d, J=17.7 Hz,1H), 4.37 (d, J=17.7 Hz, 1H), 5.07-5.13 (dd, J=5.1 and 13.2 Hz, 1H),5.21 (s, 2H), 7.22-7.51 (m, 6H), 10.96 (s, 1H); ¹³C NMR (DMSO-d₆) δ22.31, 31.16, 41.83, 45.08, 51.56, 60.01, 60.13, 69.65, 115.00, 115.17,121.54, 122.02, 126.25, 129.77, 129.93, 133.28, 134.96, 140.64, 141.08,153.46, 167.98, 170.96, 172.81; Calcd for C₂₃H₂₃N₃O₄+0.4H₂O: C, 66.94;H, 5.81; N, 10.18; Found: C, 66.80; H, 5.52; N, 10.14.

5.333-(4-((4-(MORPHOLINOMETHYL)THIAZOL-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: The mixture of ethyl 2-amino-2-thioxoacetate (2 g, 15.02 mmol)and 1,3-dichloropropan-2-one (2.193 g, 17.27 mmol) in toluene (20 mL)was heated under reflux for 3 hours. The mixture was cooled to roomtemperature, ethyl acetate (50 mL) was added. The mixture was washedwith saturated aqueous NaHCO₃ (30 mL) and brine (30 mL), and dried overMgSO₄. The solvent was evaporated and the product was purified by ISCO(120 g silica gel column, EtOAc/hexanes gradient from 0% to 20% in 30min) to give ethyl 4-(chloromethyl)thiazole-2-carboxylate as a yellowoil (2.07 g, 67% yield); ¹H NMR (CHLOROFORM-d) 1.45 (t, J=7.2 Hz, 3H,CH₃), 4.50 (q, J=7.1 Hz, 2H, CH₂), 4.78 (s, 2H, CH₂), 7.64 (s, 1H, Ar).

Step 2: To a solution of ethyl 4-(chloromethyl)thiazole-2-carboxylate(1.5 g, 7.29 mmol) in acetonitrile (30 ml) were added morpholine (1.27g, 14.59 mmol) and triethyl amine (2.03 ml, 14.59 mmol). The mixture wasstirred at room temperature overnight. The solvent was removed undervacuum, the residue was dissolved in ethyl acetate (100 mL), washed withsaturated aqueous sodium bicarbonate (2×20 ml), water (2×50 mL), brine(30 ml), and dried over MgSO₄. The solvent was removed to give ethyl4-(morpholinomethyl)thiazole-2-carboxylate (1.72 g, 92% yield); ¹H NMR(CHLOROFORM-d) δ 1.45 (t, J=7.1 Hz, 3H, CH₃), 2.47-2.66 (m, 4H, CH₂,CH₂), 3.68-3.78 (m, 4H, CH₂, CH₂), 3.80 (s, 2H, CH₂), 4.49 (q, J=7.1 Hz,2H, CH₂), 7.53 (s, 1H, Ar).

Step 3: To a solution of ethyl4-(morpholinomethyl)thiazole-2-carboxylate (0.8 g, 3.12 mmol) in THF (10ml) was slowly added a solution of Diisobutylaluminium hydride (1M intoluene, 9.36 mL, 9.36 mmol) at 0° C. The mixture was stirred at roomtemperature overnight. A solution of Rochelle's salt (1.0 M, 50 ml) andethyl acetate (50 ml) were added. The resulting suspension was stirredat room temperature for 2 hours. The clear phase separation wasachieved. The organic phase was separated and the aqueous phase wasextracted with ethyl acetate (3×40 ml). The combined organic layers werewashed with saturated aqueous NaHCO₃ (5 mL) and brine, dried over MgSO₄,and concentrated to give (4-(morpholinomethyl)thiazol-2-yl)methanol (600mg, 90% yield); ¹H NMR (CHLOROFORM-d) δ 2.44-2.63 (m, 4H, CH₂, CH₂),3.64 (s, 2H, CH₂), 3.71-3.81 (m, 4H, CH₂, CH₂), 4.95 (s, 2H, CH₂), 7.12(s, 1H, Ar).

Step 4: Polymer-supported triphenylphosphine (1.6 mmol/g, 4.13 g, 6.61mmol) was added to a stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (966 mg, 3.31mmol) in THF (40 mL) at 0° C., followed by diisopropyl azodicarboxylate(1.34 g, 6.61 mmol). After stirring for 10 minutes,(4-(morpholinomethyl)thiazol-2-yl)methanol (850 mg, 3.97 mmol) wasadded. The mixture was stirred at room temperature overnight andfiltered. The resin was rinsed with dichloromethane and methanol (2×50ml each wash). The combined filtrates and washes were concentrated andpurified by ISCO (80 g silica gel column, MeOH/CH₂Cl₂ gradient from 0%to 5% in 40 min) to give methyl5-amino-4-(4-((4-(morpholinomethyl)thiazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(360 mg, 22% yield); ¹H NMR (DMSO-d₆) δ 1.98-2.34 (m, 4H, CH₂, CH₂),2.34-2.46 (m, 4H, CH₂, CH₂), 3.50 (s, 3H, CH₃), 3.53-3.59 (m, 4H, CH₂,CH₂), 3.60 (s, 2H, CH₂), 4.33-4.65 (m, 2H, CH₂), 4.74 (d, J=5.5 Hz, 1H,CH), 5.55 (s, 2H, CH₂), 7.20 (s, 1H, NHH), 7.35 (t, J=7.2 Hz, 2H, Ar),7.44-7.57 (m, 2H, Ar), 7.61 (s, 1H, NHH).

Step 5: To a solution of methyl5-amino-4-(4-((4-(morpholinomethyl)thiazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(320 mg, 0.65 mmol) in THF (10 mL) was added potassium tert-butoxide (73mg, 0.65 mmol) at 0° C. The formed mixture was warmed to roomtemperature and stirred for 2 hours. The reaction was quenched withacetic acid (0.5 mL). The solvent was removed under vacuum. The residuewas partitioned between ethyl acetate (20 mL) and aqueous saturatedsodium bicarbonate (10 mL). The organic phase was washed with brine anddried over magnesium sulfate. The solvent was evaporated and the crudewas reslurried with acetonitrile (4 mL) to give3-(4-((4-(morpholinomethyl)thiazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (200 mg, 67% yield); mp: 218=220° C.; ¹H NMR (DMSO-d₆)δ 1.89-2.05 (m, 1H, CHH), 2.42 (d, J=4.5 Hz, 4H, CH₂), 2.44-2.49 (m, 1H,CHH), 2.55 (br. s., 1H, CHH), 2.82-3.08 (m, 1H, CHH), 3.57 (dd, J=5.2,9.7 Hz, 6H, CH₂, CH₂, CH₂), 4.18-4.55 (m, 2H, CH₂), 5.12 (dd, J=5.0,13.1 Hz, 1H, CH), 5.56 (s, 2H, CH₂), 7.38 (dd, J=5.6, 7.5 Hz, 2H, Ar),7.45-7.65 (m, 2H, Ar), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.31,31.18, 45.03, 51.62, 52.97, 57.52, 66.10, 66.93, 115.47, 115.99, 118.09,129.86, 129.99, 133.46, 152.71, 152.88, 165.07, 167.81, 170.93, 172.81;LCMS MH=457; HPLC: Waters Xterra C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240nm, Gradient (CH₃CN/0.1% HCOONH₄) 5/95 to 95/5 in 5 min, 95/5 10 min:t_(R)=3.95 (99.07%); Anal. Calcd for C₂₂H₂₄N₄O₅S: C, 57.88; H, 5.30; N,12.27; Found: C, 57.64; H, 5.36; N, 12.14.

5.341-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXY METHYL]-BENZYL}-PYRROLIDINE-2-CARBOXYLIC ACID

Step 1: To the stirred solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(900 mg, 1.89 mmol) in Acetonitrile (18 mL) was added (S)-tert-butylpyrrolidine-2-carboxylate (357 mg, 2.08 mmol) and DIPEA (0.661 ml, 3.79mmol). The resulting yellow solution was stirred at room temperatureover night and the reaction was complete. The reaction mixture wasconcentrated and dissolved in DCM (30 mL). The solution was washed byNaHCO₃ (aq, sat., 15 mL). Organic layer was dried by MgSO₄ andconcentrated to give crude1-{4-[2-(1-Carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyrrolidine-2-carboxylicacid tert-butyl ester as a light brown oil (1.23 g). The compound wasused in the next step without further purification: LCMS MH=566.

Step 2: To the stirred solution of (2S)-tert-butyl1-(4-((2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)pyrrolidine-2-carboxylate(1.071 g, 1.89 mmol) in Tetrahydrofuran (18 ml) was added Potassiumt-butyloxide (0.212 g, 1.89 mmol) in one portion at 0° C. The solutionturned to yellow immediately. The mixture was stirred at 0° C. for 10min and room temperature for 1 hr before the reaction mixture wasdiluted with DCM (70 mL). The mixture was acidified by HCl (1N, aq, 3mL) and then basified with NaHCO₃ (aq, sat., 3 mL). The mixture wasadded by brine (15 mL) and extracted. The aqueous layer was extractedwith DCM (25 mL). Organic layers were combined and dried over MgSO₄. Themixture was filtered and concentrated to give a white solid. The whitesolid was stirred in DCM (2 mL) and ether (40 mL) overnight and filteredto give1-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyrrolidine-2-carboxylicacid tert-butyl ester as a white solid (700 mg, 69% yield). The filtratewas concentrated to give second crop of1-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyrrolidine-2-carboxylicacid tert-butyl ester with some impurities as an off white solid (301mg, 30% yield): ¹H NMR (DMSO-d₆) δ 1.38 (s, 9H, CH₃, CH₃, CH₃),1.62-1.88 (m, 3H, CHH, CH₂), 1.91-2.10 (m, 2H, CH₂), 2.29-2.48 (m, 2H,CHH, CHH), 2.52-2.64 (m, 1H, CHH), 2.75-3.00 (m, 2H, CHH, CHH),3.06-3.21 (m, 1H, CHH), 3.45-3.59 (m, 1H, CHH), 3.89 (d, J=13.0 Hz, 1H,CHH), 4.18-4.48 (m, 2H, CHH, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH),5.22 (s, 2H, CH₂), 7.32 (d, J=7.6 Hz, 4H, Ar), 7.39-7.54 (m, 3H, Ar),10.97 (s, 1H, NH); LCMS MH=534.

Step 3: To the stirred solution of (2S)-tert-butyl1-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)pyrrolidine-2-carboxylate(620 mg, 1.16 mmol) in DCM (5 ml) was added hydrogen chloride, 2M indiethyl ether (5.81 ml, 11.62 mmol). The reaction mixture was stirred atroom temperature for 2 days and the reaction was complete.

The reaction mixture was concentrated and the residue was purified byISCO chromatography and prep HPLC to give1-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyrrolidine-2-carboxylic acid (170 mg, 31% yield) as anoff white solid: HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min,240 nm, 20/80 (CH₃CN/0.1% H₃PO₄): t_(R)=3.81 (96.0%); mp: 260-262° C.;¹H NMR (DMSO-d₆) δ 1.66-1.81 (m, 1H, CHH), 1.82-2.09 (m, 3H, CHH, CHH,CHH), 2.21 (dq, J=8.5, 12.7 Hz, 1H, CHH), 2.36-2.50 (m, 1H, CHH),2.57-2.69 (m, 1H, CHH), 2.80-3.02 (m, 1H, CHH), 3.24-3.38 (m, 1H, CHH),3.47-3.56 (m, 1H, CHH), 4.04 (d, J=12.8 Hz, 1H, CHH), 4.04-4.04 (m, 1H,CHH), 4.21-4.36 (m, 2H, CHH, CHH), 4.47 (d, J=17.6 Hz, 1H, CHH), 5.11(dd, J=5.1, 13.2 Hz, 1H, CHH), 5.28 (s, 2H, CH₂), 7.32-7.41 (m, 2H, Ar),7.47-7.58 (m, 5H, Ar); ¹³C NMR (DMSO-d₆) δ 22.33, 22.72, 28.52, 31.18,45.10, 51.56, 52.81, 56.90, 65.76, 69.32, 114.99, 115.25, 127.67,129.38, 129.80, 129.95, 133.30, 135.95, 136.03, 153.45, 167.97, 170.96,172.35, 172.81; LCMS MH=478; Anal. Calcd for C₂₆H₂₇N₃O₆+3H₂O+0.2CH₂Cl₂:C, 57.37; H, 6.14; N, 7.66; Found: C, 57.08; H, 5.74; N, 7.36.

5.353-[1-OXO-4-(4-[1,2,3]TRIAZOL-1-YLMETHYL-BENZYLOXY)-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the stirred solution of 1H-1,2,3-triazole (139 mg, 2.020mmol) in Acetonitrile (15 mL) was added methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(800 mg, 1.683 mmol) and DIPEA (0.588 ml, 3.37 mmol) at roomtemperature. The resulting clear solution was stirred at roomtemperature for 19 hrs. To the mixture was added DCM (50 mL). Theorganic layer was extracted with NaHCO₃ (sat. aq, 5 mL) and brine (10mL). The organic layer was concentrated for ISCO purification to give4-Carbamoyl-4-[1-oxo-4-(4-[1,2,3]triazol-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a white solid (710 mg, 70% yield); LCMS MH=464; ¹HNMR (DMSO-d₆) δ 1.96-2.31 (m, 4H, CH₂, CH₂), 3.50 (s, 3H, CH₃), 4.39 (d,J=17.8 Hz, 1H, CHH), 4.52 (d, J=17.6 Hz, 1H, CHH), 4.67-4.78 (m, 1H,CHH), 5.23 (s, 2H, CH₂), 5.63 (s, 2H, CH₂), 7.18 (s, 1H, Ar), 7.23-7.37(m, 4H, Ar), 7.40-7.53 (m, 3H, Ar), 7.57 (s, 1H, NHH), 7.75 (d, J=0.8Hz, 1H, Ar), 8.20 (d, J=0.8 Hz, 1H, Ar).

Step 2: To the stirred solution of methyl4-(4-(4-((1H-1,2,3-triazol-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(710 mg, 1.53 mmol) in Tetrahydrofuran (15 ml) was added KOtBu (200 mg,1.78 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 4 hrs,KOtBu (40 mg, 0.36 mmol) was added. 30 mins later, the reaction mixturewas diluted by EtOAc (50 mL) and acidified by HCl (1N, aq, 4 mL)followed by the addition of NaHCO₃ (sat., aq, 4 mL) and brine (15 mL).The mixture was extracted and the organic layer was dried over MgSO₄.The mixture was filtered and the filtrate was concentrated under vacuoto give a white solid. The white solid was suspended in ether (30 mL)and stirred over weekend. The suspension was filtered to give3-[1-Oxo-4-(4-[1,2,3]triazol-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (440 mg, 67% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 30/70, CH₃CN/0.1% H₃PO₄), 4.84 min(98.4%); mp: 133-135° C.; ¹H NMR (DMSO-d₆) δ 1.90-2.03 (m, 1H, Mo₁),2.35-2.48 (m, 1H, CHH), 2.53-2.63 (m, 1H, CHH), 2.81-3.00 (m, 1H, CHH),4.24 (d, J=17.6 Hz, 1H, CHH), 4.40 (d, J=17.6 Hz, 1H, CHH), 5.10 (dd,J=5.1, 13.2 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 5.63 (s, 2H, CH₂),7.26-7.37 (m, 4H, Ar), 7.43-7.53 (m, 3H, Ar), 7.75 (d, J=0.8 Hz, 1H,CH), 8.20 (d, J=0.9 Hz, 1H, CH), 10.96 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.31, 31.18, 45.06, 51.56, 52.26, 69.12, 114.90, 115.26, 124.94,127.95, 128.06, 129.78, 129.93, 133.30, 133.52, 135.95, 136.51, 153.36,167.97, 170.95, 172.81; LCMS MH=432; Anal. Calcd for C₂₃H₂₁N₅O₄+0.7H₂O:C, 62.21; H, 5.08; N, 15.77; Found: C, 62.07; H, 4.88; N, 15.46.

5.363-[4-(4-[1,4]OXAZEPAN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the stirred solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(600 mg, 1.26 mmol) in Acetonitrile (10 mL) at room temperature wasadded by 1,4-oxazepane hydrochloride (208 mg, 1.51 mmol) and DIPEA (0.44ml, 2.52 mmol). The reaction mixture was stirred at room temperatureovernight and diluted by DCM (50 mL). The mixture was washed with NaHCO₃(aq, sat. 5 mL) and brine (15 ml). The organic layer was dried by MgSO₄and concentrated under vacuo to give crude4-Carbamoyl-4-[4-(4-[1,4]oxazepan-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a sticky oil (810 mg). The compound was used in thenext step without further purification; LCMS MH=496.

Step 2: To the stirred suspension of methyl4-(4-(4-((1,4-oxazepan-4-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(625 mg, 1.26 mmol) in Tetrahydrofuran (10 mL) at 0° C. was added KOtBu(142 mg, 1.26 mmol) in one portion. The reaction mixture was stirred at0° C. for 1 hour and KOtBu (70 mg) was added. 15 minutes later, thereaction mixture was diluted by EtOAc (50 mL) and acidified by HCl (aq,1N, 3 mL) followed by the addition of NaHCO₃ (aq, sat., 3 mL) and brine(10 mL). The mixture was extracted and the organic layer was dried byMgSO₄. The mixture was filtered and the filtrate was concentrated downto give white solid. The solid was stirred in diethyl ether (20 mL) andfiltered to give3-[4-(4-[1,4]Oxazepan-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (484 mg, 83% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 5 to 95% in 10 mins, (CH₃CN/0.1%H₃PO₄), 5.7 min (95.9%); mp: 119-121° C.; ¹H NMR (DMSO-d₆) δ 1.72-1.88(m, 2H, CH₂), 1.92-2.04 (m, 1H, CHH), 2.35-2.47 (m, 1H, CHH), 2.53-2.69(m, 5H, CH₂, CH₂, CHH), 2.83-2.99 (m, 1H, CHH), 3.54-3.65 (m, 4H, CH₂,CH₂), 3.69 (t, J=6.0 Hz, 2H, CH₂), 4.25 (d, J=17.6 Hz, 1H, CHH), 4.42(d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.23 (s,2H, CH₂), 7.26-7.39 (m, 4H, Ar), 7.40-7.54 (m, 3H, Ar), 10.97 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 22.34, 29.28, 31.18, 45.07, 51.55, 53.24,57.10, 60.98, 67.69, 68.33, 69.38, 114.94, 115.22, 127.66, 128.73,129.78, 129.93, 133.30, 135.24, 139.05, 153.49, 167.99, 170.96, 172.81;LCMS MH=464; Anal. Calcd for C₂₆H₂₉N₃O₅+0.5H₂O: C, 66.09; H, 6.40; N,8.89; Found: C, 65.83; H, 6.04; N, 8.60.

5.373-[1-OXO-4-(4-1,2,3]TRIAZOL-2-YLMETHYL-BENZYLOXY)-1,3-DIHYDRO-ISOINDOL-2-YL-PIPERIDINE-2,6-DIONE

Step 1. To the stirred solution of 1H-1,2,3-triazole (139 mg, 2.020mmol) in Acetonitrile (15 mL) was added by methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(800 mg, 1.683 mmol) and DIPEA (0.588 ml, 3.37 mmol) at roomtemperature. The resulting clear solution was stirred at roomtemperature for 19 hrs and another same reaction mixture (12.5% scale ofthis one) followed by 1H-1,2,3-trazole (60 mg, 0.87 mmol) was added. Thecombined reaction mixture was stirred at room temperature overnight andthen added by DCM (50 mL), NaHCO₃ (sat. aq, 5 mL) and brine (10 mL). Themixture was extracted and the organic layer was concentrated for ISCOpurification to give4-Carbamoyl-4-[1-oxo-4-(4-[1,2,3]triazol-2-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a sticky clear oil (102 mg, 9% yield); LCMS MH=464;¹H NMR (DMSO-d₆) δ 1.97-2.31 (m, 4H, CH₂, CH₂), 3.50 (s, 3H, CH₃), 4.39(d, J=17.6 Hz, 1H, CHH), 4.52 (d, J=17.8 Hz, 1H, CHH), 4.66-4.78 (m, 1H,CHH), 5.23 (s, 2H, CH₂), 5.67 (s, 2H, CH₂), 7.13-7.22 (m, 1H, NHH),7.23-7.32 (m, 4H, Ar), 7.40-7.52 (m, 3H, Ar), 7.58 (s, 1H, NHH), 7.81(s, 2H, Ar).

Step 2. To the stirred solution of methyl4-(4-(4-((2H-1,2,3-triazol-2-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(100 mg, 0.216 mmol) in Tetrahydrofuran (Volume: 4 ml) at 0° C. wasadded KOtBu (29.1 mg, 0.259 mmol) in one portion. The reaction mixturewas stirred at 0° C. for 1 hr. KOtBu (30 mg, 0.26 mmol) was added to thereaction mixture. The reaction mixture was stirred at 0° C. for 30minutes and then diluted by EtOAc (40 mL). The resulting solution wasacidified by HCl (aq, 1N, 2 mL) and then basified by NaHCO₃ (aq, sat., 2mL), and followed by the addition of brine (10 mL). The mixture wasextracted and the organic layer was dried over MgSO₄. The suspension wasfiltered and concentrated to give a white solid. The white solid wassuspended in diethyl ether (10 mL) and stirred at room temperatureovernight. The mixture was filtered to give3-[1-oxo-4-(4-[1,2,3]triazol-2-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (56 mg, 32% yield); HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, 40/60, (CH₃CN/0.1% H₃PO₄), 3.71 min (96.8%);mp: N/A; ¹H NMR (DMSO-d₆) δ 1.90-2.04 (m, 1H, CHH), 2.35-2.47 (m, 1H,CHH), 2.54-2.63 (m, 1H, CHH), 2.81-3.00 (m, 1H, CHH), 4.24 (d, J=17.6Hz, 1H, CHH), 4.40 (d, J=17.6 Hz, 1H, CHH), 5.10 (dd, J=5.1, 13.2 Hz,1H, CHH), 5.23 (s, 2H, CH₂), 5.67 (s, 2H, CH₂), 7.21-7.38 (m, 4H, Ar),7.41-7.54 (m, 3H, Ar), 7.81 (s, 2H, triazole), 10.96 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 22.31, 31.16, 45.04, 51.55, 57.23, 69.14, 114.90,115.25, 127.95, 129.78, 129.94, 133.19, 134.70, 135.70, 136.39, 152.69,167.98, 170.93, 172.80; LCMS MH=432; Anal. Calcd for C₂₃H₂₁N₅O₄: C,64.03; H, 4.91; N, 16.23; Found: N/A.

5.38 PREPARATION OF 3-(4-((6-(MORPHOLINOMETHYL)BENZOFURAN-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-hydroxy-4-methylbenzaldehyde (4.2 g, 31.1 mmol),potassium carbonate (5.6 g, 40.5 mmol) and molecular sieve (4.0 g) inDMF (40 mL) was heated to 50° C. Ethyl bromoacetate (5.2 g, 31.1 mmol)was added slowly at 50-55° C. The reaction mixture was heated at 75° C.for 20 min then at 110° C. for 1 h. The reaction mixture was cooled toroom temperature and diluted with EtOAc (100 mL). The mixture wasfiltered and the solid was washed with EtOAc (50 mL). The filtrate waswashed with water (3×60 mL), brine (60 mL) and dried. The solvent wasremoved in vacuo and the crude mixture was purified by chromatography(SiO₂, CH₂Cl₂) to give ethyl 6-methylbenzofuran-2-carboxylate (1 g,16%): ¹H NMR (CDCl₃) δ 1.42 (t, J=6 Hz, 3H), 2.49 (s, 3H), 4.40-4.47 (q,J=6 Hz, 2H), 7.11-7.14 (d, J=9 Hz, 1H), 7.38 (s, 1H), 7.48 (s, 1H),7.53-7.56 (t, J=9 Hz, 1H).

Step 2: A mixture of ethyl 6-methylbenzofuran-2-carboxylate (0.9 g, 4.6mmol) and N-bromosuccinimide (1 g, 6.0 mmol) in CCl₄ (20 mL) was heatedat 70° C. in an oil bath with a 300 W bulb shining to reaction mixturefor 4 h. The reaction mixture was cooled and filtered and the solid waswashed with CH₂Cl₂ (30 mL). The filtrate was concentrated in vacuo andthe crude mixture was purified by chromatography (SiO₂, 10%EtOAc/hexane) to give ethyl 6-(bromomethyl)benzofuran-2-carboxylate (1.3g, 100%): H NMR (DMSO-d₆) δ 1.34 (t, J=6 Hz, 3H), 4.34-4.41 (q, J=6 Hz,2H), 4.87 (s, 2H), 7.44-7.53 (m, 1H), 7.76-7.96 (m, 3H).

Step 3: A mixture of potassium carbonate (3.6 g, 26 mmol), morpholine(1.0 g, 11.3 mmol) and catalytic amount of 18-crown-6 in acetone (15 mL)was heated at 60° C. in an oil bath. A solution of ethyl6-(bromomethyl)benzofuran-2-carboxylate (2.0 g, 7.1 mmol) in acetone (15mL) was added slowly and the mixture was heated at 60° C. oil bath for 3h. The reaction mixture was cooled to room temperature and filtered. Thefiltrate was concentrated and the residue was dissolved in EtOAc (100mL) and washed with water (2×30 mL), brine (30 mL) and dried. Solventwas removed in vacuo and the residue was purified by chromatography(SiO₂, 30% EtOAc/hexane for 15 min then to 60% over 20 min and hold for15 min) to give ethyl 6-(morpholinomethyl)benzofuran-2-carboxylate (1.2g, 60%): ¹H NMR (CDCl₃) δ 1.43 (t, 6 Hz, 3H), 2.45-2.48 (m, 4H), 3.62(s, 2H), 3.71-3.73 (m, 4H), 4.41-4.48 (q, J=6 Hz, 2H), 7.27-7.31 (m,1H), 7.50 (s, 1H), 7.58-7.62 (m, 2H).

Step 4: A solution of LiAlH₄/THF (1M, 5.4 mL, 5.4 mmol) in THF (10 mL)was cooled in an ice bath to 5° C. A solution of ethyl6-(morpholinomethyl)benzofuran-2-carboxylate (1.2 g, 4.2 mmol) in THF(20 mL) was added dropwise at 5-10° C. The reaction mixture was stirredin an ice bath for 30 min then carefully quenched with water (10 mL).The mixture was diluted with sat. Na₂CO₃ (40 mL) and CH₂Cl₂ (50 mL) andthe aq. layer was extracted with CH₂Cl₂ (3×30 mL). The combined CH₂Cl₂solution was washed with water (40 mL), brine (40 mL) and dried. Solventwas removed to give (6-(morpholinomethyl)benzofuran-2-yl)methanol (0.9g, 88%): ¹H NMR (CDCl₃) δ 2.40 (b, 1H), 2.44-2.47 (m, 4H), 3.59 (s, 2H),3.71-3.72 (m, 4H), 4.75 (s, 2H), 6.63 (s, 1H), 7.18-7.20 (m, 1H),7.45-7.48 (m, 2H).

Step 5: A mixture of Triphenylphosphine-polymer bound (3.5 g, 4.3 mmol)in THF (40 mL) was cooled in an ice bath to 3° C. Diisopropylazodicarboxylate (0.8 g, 4.6 mmol) was added slowly at 3-5° C. Afterstirred at 3° C. for 10 min, a solution of(6-(morpholinomethyl)benzofuran-2-yl)methanol (0.9 g, 3.6 mmol) andmethyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.9g, 3.1 mmol) in THF (60 mL) was added at 3-8° C. After stirred for 10min, the ice bath was removed and the mixture was stirred at roomtemperature overnight. The reaction mixture was filtered and the solidwas washed with CH₂Cl₂ (30 mL). The combined filtrates was concentratedand the resulting residue was dissolved in CH₂Cl₂ (80 mL) and washedwith sat. NaHCO₃ (40 mL), water (40 mL), brine (40 mL) and dried. Thesolvent was removed in vacuo and the residue was purified bychromatography (SiO₂, CH₂Cl₂ for 5 min then to 3% CH₃OH/CH₂Cl₂ over 5 inand hold for 20 min then to 5% over 5 in and hold for 20 min) to givemethyl5-amino-4-(4-((6-(morpholinomethyl)benzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.0 g, 44%).

Step 6: A mixture of methyl5-amino-4-(4-((6-(morpholinomethyl)benzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.0 g, 1.9 mmol) and potassium carbonate (0.3 g, 1.9 mmol) in DMF (10mL) was heated at 80° C. oil bath for 3 h. The reaction mixture wascooled to room temperature and diluted with EtOAc (80 mL). The mixturewas filtered and the filtrate was washed with water (3×35 mL), brine (35mL) and dried. The solvent was removed and the residue was purified bychromatography (SiO₂, CH₂Cl₂ for 5 min then to 3% CH₃OH/CH₂Cl₂ over 5min and hold for 15 min then to 5% over 5 min and hold for 20 min) togive3-(4-((6-(morpholinomethyl)benzufuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.24 g, 26%): mp 142-144° C.; ¹H NMR (DMSO-d₆) δ 1.95-1.99 (m, 1H),2.35-2.59 (m, 1H), 2.84-2.96 (m, 1H), 3.33 (s, 4H), 3.56 (b, 2H), 4.26(d, J=17.7 Hz, 1H), 4.36 (d, J=17.4 Hz, 1H), 5.07-5.13 (dd, J=5.1 and13.2 Hz, 1H), 5.42 (s, 2H), 7.09 (s, 1H), 7.23 (b, 1H), 7.34-7.37 (dd,J=0.9 and 6.9 Hz, 1H), 7.46-7.61 (m, 4H), 10.96 (s, 1H); ¹³C NMR(DMSO-d6) δ 22.29, 31.17, 45.04, 51.56, 53.05, 62.50, 66.15, 107.01,111.38, 115.10, 115.66, 121.02, 124.22, 126.55, 129.81, 129.93, 133.43,135.00, 152.55, 152.96, 154.67, 167.87, 170.93, 172.80; Calcd forC₂₇H₂₇N₃O₆+0.5H₂O: C, 65.06; H, 5.66; N, 8.43; Found: C, 64.97; H, 5.49;N, 8.39.

5.39 3-(1-OXO-4-(4-(THIOMORPHOLINOMETHYL)BENZYLOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1Methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate

1,4-bis(Bromomethyl)benzene (2.71 g, 10.26 mmol) was suspended in dryacetonitrile (40 mL). The slurry was warmed up to 60° C. until fulldissolution occurred (˜15 min). The temperature was reduced to 50° C.and to the solution was added K₂CO₃ (0.473 g, 3.42 mmol) as a solidfollowed by methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1 g, 3.42mmol, preparation described herein). The resulting white slurry wasstirred at 50° C. for ˜3 h at which time LCMS indicated the phenolstarting material was consumed. The crude reaction mixture was swirledand filtered with suction. The remaining solid in flask and on thefilter funnel was rinsed with minimal MeCN (˜5 mL). The filtrate wasconcentrated in vacuo to give 2.6 g of a white solid. The solid wasdissolved in minimal DCM and purified using a SiO₂ flash column(CombiFlash, 40 g SiO₂ prepacked column). The column was eluted with100% DCM for −15 min, a gradient to 5% MeOH in DCM over 5 min, and thenheld at 5% MeOH in DCM. Fractions were combined and concentrated to givemethyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas a white solid (1.3 g, 80% yield): ¹H NMR (DMSO-d₆) δ 1.94-2.34 (m,4H, CH₂, CH₂), 3.50 (s, 3H, CH₃), 4.33-4.62 (m, 2H, CH₂), 4.72 (s, 2H,CH₂), 5.25 (s, 2H, CH₂), 5.27-5.36 (m, 1H, CH), 7.19 (br. s., 1H, NH),7.23-7.36 (m, 2H, Ar), 7.40-7.70 (m, 6H, Ar, NH); LC/MS M+H=475, 477.

Step 2.3-(4-(4-(Bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione:Methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(2.05 g, 4.31 mmol) was dissolved in THF (50 mL) and the solution wascooled in dry ice/acetone bath to −76° C. While stirring, solid KOBu(0.532 g, 4.74 mmol) was added in one portion to the clear solution. Thereaction mixture became a pale yellow color and was stirred for −90 minat −76° C. A cooled solution of 1N aq HCl (20 mL) was rapidlytransferred to the reaction mixture, maintaining temperature at −76° C.The mixture immediately turned milky white and the dry CO₂/acetone bathwas removed, allowing the mixture to warm up to while stirring. Themixture was concentrated on a rotovap to remove most of THF(concentrated to a fixed volume at 160 mbar and water bath ˜35° C.).Upon concentration of reaction mixture, a white solid precipitated out.The white slurry was diluted with more water (˜80 mL) and then suctionfiltered. The cake was washed with copious water (total filtrate volume˜150 mL) and suction dried. The cake was washed with Et₂O (˜50 mL),suction dried and then placed in vacuum oven at 40° C. overnight to give3-(4-(4-(Bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (1.8 g, 94% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 50/50 CH₃CN/0.1% H₃PO₄, 3.70 min (97.9%);mp, 123-125° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.05 (m, 1H, CHH), 2.32-2.48(m, 1H, CHH), 2.52-2.64 (m, 1H, CHH), 2.78-3.04 (m, 1H, CHH), 4.26 (d,J=17.6 Hz, 1H, CHH), 4.43 (d, J=17.6 Hz, 1H, CHH), 4.72 (s, 2H, CH₂),5.11 (dd, J=5.0, 13.1 Hz, 1H, CH), 5.25 (s, 2H, CH₂), 7.24-7.36 (m, 2H,Ar), 7.41-7.54 (m, 5H, Ar), 10.83-11.07 (m, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.33, 31.18, 34.15, 45.06, 51.56, 69.12, 114.94, 115.28, 127.95,128.33, 129.41, 129.80, 131.93, 133.31, 136.78, 153.36, 167.97, 170.95,172.81; LC/MS M+H=443, 445. The solid was used in the next step withoutfurther purification.

Step 3.3-(1-Oxo-4-(4-(thiomorpholinomethyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dione:

In a 20-mL reaction vial, thiomorpholine (62.8 mg, 0.609 mmol) was addedto a solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(150 mg, 0.338 mmol) in MeCN (5 mL). The clear reaction mixture wasstirred at room temperature for 2 h. The reaction mixture was cooled to0° C. and quenched with addition of 1.5 mL of glatial acetic acid. Aslurry formed which was partitioned between EtOAc (100 mL) and 1N NaHCO₃(30 mL). The organic layer was washed with brine, dried (Na₂SO₄), andconcentrated in vacuo to give a glassy solid. The solid was trituratedwith water and sonicated to give a free flowing solid. This solid wascollected by filtration, suction dried, and then dried in vacuum oven at40° C. to give3-(1-oxo-4-(4-(thiomorpholinomethyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (127 mg, 81% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 17/83 CH₃CN/0.1% H₃PO₄, 5.05 min (97.0%);mp: 134-136° C.; ¹H NMR (DMSO-d₆) δ 1.86-2.05 (m, 1H, CHH), 2.32-2.47(m, 1H, CHH), 2.60 (s, 9H, 4×CH₂, CHH), 2.80-3.00 (m, 1H, CHH), 3.49 (s,2H, CH₂), 4.25 (d, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.4 Hz, 1H, CHH),5.11 (dd, J=4.8, 12.9 Hz, 1H, CH), 5.22 (s, 2H, CH₂), 7.01-7.38 (m, 4H,Ar), 7.38-7.65 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.33, 27.14, 31.16, 45.06, 51.55, 54.36, 62.23, 69.38, 114.94, 115.20,127.63, 128.84, 129.78, 129.93, 133.28, 135.22, 137.89, 153.48, 167.97,170.95, 172.81; LC/MS M+H=466; Anal Calcd for C₂₅H₂₇N₃O₄S+0.25H₂O: C,63.88; H, 5.90; N, 8.94; S, 6.82; Found: C, 63.85; H, 5.93; N, 8.67; S,6.50.

5.403-{1-OXO-4-[4-(1-OXO-THIOMORPHOLIN-4-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

In a 20-mL reaction vial, N,N-diisopropylethylamine (0.197 mL, 1.128mmol) was added to a suspension of 1-oxo-thiomorpholine hydrochloride(97 mg, 0.620 mmol) in MeCN (5 mL). The mixture was sonicated at roomtemperature to break up solid. Upon full dissolution of the,3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(250 mg, 0.564 mmol) was added to the solution in one portion and theresulting mixture was stirred at room temperature. After about 1 hour,MeCN (˜5 mL) was added to improve stirring. The mixture was stirred foranother 4 hours at room temperature and then diluted with EtOAc (15 mL).The slurry was stirred for a few minutes then filtered on a fine-porefilter funnel with suction. The cake was washed with a small portion ofEtOAc (˜5 mL), suction dried, and then dried further in vacuum oven at40° C. to give3-{1-oxo-4-[4-(1-oxo-thiomorpholin-4-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (110 mg, 40% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 m/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 4.25 min (98.9%);mp: 170-172° C., ¹H NMR (DMSO-d₆) δ 1.90-2.05 (m, 1H, CHH), 2.36-2.47(m, 1H, CHH), 2.53-2.66 (m, 3H, CH₂, CHH), 2.66-2.77 (m, 2H, CH₂),2.79-3.01 (m, 5H, CH₂, CH₂, CHH), 3.57 (s, 2H, CH₂), 4.25 (d, J=17.6 Hz,1H, CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H,CH), 5.23 (s, 2H, CH₂), 7.26-7.39 (m, 4H, Ar), 7.40-7.54 (m, 3H, Ar),10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 43.56, 45.07,45.51, 51.55, 61.15, 69.36, 114.96, 115.22, 127.67, 128.92, 129.80,129.95, 133.28, 135.38, 137.67, 153.48, 167.97, 170.96, 172.81; LC/MSM+H=482; Anal Calcd for C₂₅H₂₇N₃O₅S+1.0H₂O: C, 60.10; H, 5.85; N, 8.41;S, 6.42; Found: C, 59.94; H, 5.52; N, 8.26; S, 6.45.

5.41(S)-2-(3-METHYL-2,6-DIOXOPIPERIDIN-3-YL)-4-(4-MORPHOLINOMETHYL)BENZYLOXY)ISOINDOLINE-1,3-DIONE

Step 1: In a 250 ml RBF, dimethyl 3-hydroxyphthalate (1 g, 4.76 mmol)and triphenyl phosphine on polystyrene (1.6 mmol/g resin) (2.98 g, 4.76mmol) were slurried in THF (40 ml) at room temperature. The mixture wascoolded at 0° C. and DIAD (1.850 ml, 9.52 mmol) was added via syringe,after 10 minutes, (4-(morpholinomethyl)phenyl) methanol (0.986 g, 4.76mmol) in THF (10 ml) was added, and the mixture was stirred at roomtemperature overnight. The reaction mixture was filtered, the resin wasrinsed with washes of DCM and MeOH (2×50 ml each wash), the combinedfiltrates and washes were concentrated in vacuo to a syrup. The residuewas purified by ISCO (80 g column, MeOH in DCM gradient from 0-5 in 50min, 5% MeOH in DCM 20 min) to give dimethyl3-(4-(morpholinomethyl)benzyloxy)phthalate (770 mg, 41% yield). ¹H NMR(DMSO-d₆) δ 2.29-2.40 (m, 4H, CH₂, CH₂), 3.45 (s, 2H, CH₂), 3.53-3.60(m, 4H, CH₂, CH₂), 3.79 (s, 3H, CH₃), 3.82 (s, 3H, CH₃), 5.21 (s, 2H,CH₂), 7.33 (d, J=0.9 Hz, 4H, Ar), 7.44-7.59 (m, 3H, Ar).

Step 2: To a solution of dimethyl 3-(4-(morpholinomethyl)benzyloxy)phthalate (770 mg, 1.928 mmol) in EtOH (20 ml, 343 mmol), was added NaOH(3N, 10 mL, pre-made from 12 N solution). The mixture was refluxed for 1hour. The reaction mixture was evaporated to dryness in vacuum. HCl (1N)was added to the residue and adjusted pH to 3, and the precipitate wascollected by filtration to give 3-(4-(morpholinomethyl)benzyloxy)phthalic acid as a white solid (350 mg, 49% yield). ¹H NMR(DMSO-d₆) δ 2.27-2.43 (m, 4H, CH₂, CH₂), 3.49 (s, 2H, CH₂), 3.53-3.65(m, 4H, CH₂, CH₂), 5.17 (s, 2H, CH₂), 7.16-7.63 (m, 7H, Ar).

Step 3: The mixture of 3-(4-(morpholinomethyl)benzyloxy)phthalic acid(300 mg, 0.808 mmol) and (S)-3-amino-3-methylpiperidine-2,6-dionehydrobromide (198 mg, 0.889 mmol) in pyridine (20 ml) was heated toreflux for 2 days and cooled to room temperature. Pyridine was strippedof under reduced pressure, the residue was partitioned between EtOAc (50ml) and sodium bicarbonate (10 ml), the organic layer was separated andwashed with water (2×10 ml), brine (10 ml), and dried (MgSO₄). Thesolvent was evaporated under reduced pressure, the residue was purifiedby ISCO (12 g column, MeOH in DCM gradient from 0-3% in 25 min) to give(S)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-4-(4-(morpholinomethyl)benzyloxy)isoindoline-1,3-dione(100 mg, 26% yield). mp: 178-180° C.; ¹H NMR (DMSO-d₆) δ 1.88 (s, 3H,CH₃), 1.98-2.12 (m, 1H, CHH), 2.29-2.42 (m, 4H, CH₂, CH₂), 2.52-2.83 (m,3H, CHH, CHH, CHH), 3.47 (s, 2H, CH₂), 3.53-3.66 (m, 4H, CH₂, CH₂), 5.31(s, 2H, CH₂), 7.29-7.51 (m, 5H, Ar), 7.57 (d, J=8.5 Hz, 1H, Ar), 7.80(dd, J=7.4, 8.5 Hz, 1H, Ar), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.96, 28.55, 29.03, 53.11, 58.53, 62.06, 66.13, 69.93, 115.09, 116.14,119.86, 127.35, 129.01, 133.24, 134.74, 136.83, 137.69, 155.33, 166.06,167.42, 172.10, 172.27; MH=478; HPLC: Waters Xterra C-18, 3.9×150 mm, 5μm, 1 mL/min, 240 nm, Gradient (CH₃CN/0.1% HCOONH₄) 5/95 to 95/5 in 5min, 95/5 10 min: t_(R)=3.72 (100%); Anal. Calcd for C₂₆H₂₇N₃O₆C, 65.40;H, 5.70; N, 8.80; Found: C, 65.28; H, 5.67; N,8.60.

5.423-[1-OXO-4-(4-[1,2,4]TRIAZOL-1-YLMETHYL-BENZYLOXY)-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Preparation of4-Carbamoyl-4-[1-oxo-4-(4-[1,2,4]triazol-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

To a solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.804 g, 1.691 mmol) in acetonitrile (20 ml) was added1H-1,2,4-triazole (0.350 g, 5.07 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.839 ml, 5.07 mmol) at roomtemperature. The mixture was stirred at room temperature for two daysand then diluted by methylene chloride (50 mL) and washed with saturatedsodium bicarbonate (10 mL) and brine (10 mL). Organic layer wasconcentrated and purified on silica gel column (MeOH/CH₂Cl₂ gradientfrom 1% to 9% in 50 min) to give4-Carbamoyl-4-[1-oxo-4-(4-[1,2,4]triazol-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as an oil (0.53 g, 67% yield); ¹H NMR (DMSO-d₆) δ1.96-2.36 (m, 4H, CHH, CHH, CHH, CHH), 3.50 (s, 3H, CH₃), 4.32-4.58 (m,2H, CH₂), 4.72 (dd, J=4.9, 10.4 Hz, 1H, NCH), 5.23 (s, 2H, CH₂),5.37-5.50 (m, 2H, CH₂), 7.13-7.21 (m, 1H, NHH), 7.24-7.36 (m, 4H, Ar),7.40-7.53 (m, 3H, Ar), 7.57 (br. s., 1H, NHH), 7.98 (s, 1H, Ar), 8.66(s, 1H, Ar). It was used in the next step without further purification.

Step 2: Preparation of3-[1-Oxo-4-(4-[1,2,4]triazol-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione

To a stirred solution of methyl4-(4-(4-((1H-1,2,4-triazol-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(0.49 g, 1.057 mmol) in THF (20 ml) in an ice-bath was added potassium2-methylpropan-2-olate (0.119 g, 1.057 mmol). After stirring for 10minutes, 1 N HCl (2 ml) was added, neutralized by saturated sodiumbicarbonate (3 ml), and stirred with ethyl acetate (50 ml). The organicphase was separated, washed with brine (10 ml) and evaporated to a whitesolid, which was purified on silica gel column (MeOH/CH₂Cl₂ gradientfrom 0% to 4% in 40 min) to give3-[1-Oxo-4-(4-[1,2,4]triazol-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (0.177 g, 39% yield); mp, 233-235° C.; HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 5.43min (96.4%); H NMR (DMSO-d₆) δ 1.90-2.05 (m, 1H, CHH), 2.36-2.48 (m, 1H,CHH), 2.53-2.64 (m, 1H, CHH), 2.82-2.99 (m, 1H, CHH), 4.17-4.48 (m, 2H,CH₂), 5.10 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 5.43 (s,2H, CH₂), 7.25-7.37 (m, 4H, Ar), 7.42-7.55 (m, 3H, Ar), 7.98 (s, 1H,Ar), 8.67 (s, 1H, Ar), 10.96 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.35,31.20, 45.08, 51.58, 51.78, 69.19, 114.95, 115.27, 128.02, 129.81,129.97, 133.32, 136.09, 136.35, 144.23, 151.72, 153.40, 167.99, 170.96,172.82; LC/MS (M+1)+=432; Anal Calcd for C₂₃H₂₁N₅O₄+0.2H₂O: C, 63.50; H,4.96; N, 16.10; Found: C, 63.11; H, 4.89; N, 16.00.

5.431-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYL}-PYRROLIDINE-2-CARBOXYLIC ACID

Step 1:1-{4-[2-(1-Carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyrrolidine-2-carboxylicacid tert-butyl ester

To the stirred mixture of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (798 mg, 1.679 mmol) and (R)-tert-butylpyrrolidine-2-carboxylate hydrochloride (418 mg, 2.015 mmol) inAcetonitrile (12 mL) at room temperature was added by DIPEA (0.586 ml,3.36 mmol). The resulting solution was stirred at room temperature for19 hrs before it was diluted by DCM (50 mL). The solution was washedwith NaHCO₃ (sat, aq, 5 mL) and brine (15 mL). Organic layer was driedby MgSO₄ and concentrated under vacuo. The residue was purified by ISCOchromatography to give1-{4-[2-(1-Carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyrrolidine-2-carboxylicacid tert-butyl ester as a clear oil (840 mg, 88% yield) which was usedin the next step without further purification; LCMS MH=566; ¹H NMR(DMSO-d₆) δ 1.38 (s, 9H, CH₃, CH₃), 1.64-1.86 (m, 3H, CH, CH₂),1.93-2.12 (m, 2H, CH₂), 2.13-2.22 (m, 1H, CHH), 2.22-2.30 (m, 2H, CH₂),2.36 (q, J=7.7 Hz, 1H, CHH), 2.77-2.92 (m, 1H, CHH), 3.13 (dd; J=5.0,8.8 Hz, 1H, CHH), 3.44-3.59 (m, 4H, CHH, CH₃), 3.88 (d, J=13.2 Hz, 1H,CHH), 4.39 (d, J=17.8 Hz, 1H, CHH), 4.53 (d, J=17.6 Hz, 1H, CHH), 4.72(dd, J=4.7, 10.2 Hz, 1H, CHH), 5.21 (s, 2H, CH₂), 7.18 (s, 1H, NHH),7.24-7.37 (m, 4H, Ar), 7.39-7.53 (m, 3H, Ar), 7.58 (s, 1H, NHH).

1-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyrrolidine-2-carboxylicacid tert-butyl ester

To the stirred solution of (2R)-tert-butyl1-(4-((2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)pyrrolidine-2-carboxylate(840 mg, 1.485 mmol) in Tetrahydrofuran (13 mL) at 0° C. was added KOtBu(167 mg, 1.485 mmol). The reaction mixture was stirred at 0° C. for 20mins before it was diluted by EtOAc (50 mL). The mixture was acidifiedby HCl (1N, aq, 3 mL) followed by addition of NaHCO₃ (aq, sat, 3 mL) andbrine (15 mL). The mixture was extracted and the organic layer waswashed with NaCl (10 ml brine+10 mL water). Organic layer was dried byMgSO₄ and concentrated under vacuo to give1-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyrrolidine-2-carboxylicacid tert-butyl ester as a sticky clear oil (810 mg, 102% crude yield)which was used in the next step without further purification; LCMSMH=534.

Step 3:1-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyrrolidine-2-carboxylicacid

To the solution of (2R)-tert-butyl1-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)pyrrolidine-2-carboxylate(0.795 g, 1.489 mmol) in DCM (Volume: 5 ml) was added by HCl, 2M indiethyl ether (11.17 ml, 22.34 mmol) at room temperature for 4 days andthe reaction mixture was concentrated in vacuo and then added fresh 2MHCl (ether, 15 mL). The suspension was stirred at room temperature forat room temperature over night. The reaction mixture was concentrated invacuo and the residue was stirred in acetonitrile (15 mL) for 4 hrs. Themixture was filtered to give1-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-pyrrolidine-2-carboxylicacid as an off white solid (420 mg, 57.5% yield); HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 18/82, (CH₃CN/0.1% H₃PO₄),4.84 min (96.67%); mp: 233-235° C.; ¹H NMR (DMSO-d₆) δ 1.75-2.06 (m, 4H,CHH, CHH, CH₂), 2.45 (d, J=13.4 Hz, 2H, CHH, CHH), 2.54-2.65 (m, 1H,CHH), 2.83-3.02 (m, 1H, CHH), 3.11-3.27 (m, 1H, CHH), 3.32-3.46 (m, 1H,CHH), 4.18-4.34 (m, 3H, CHH, CHH, CHH), 4.39-4.52 (m, 2H, CHH, CHH),5.12 (dd, J=5.0, 13.1 Hz, 1H, CHH), 5.29 (s, 2H, CH₂), 7.33 (dd, J=4.9,7.7 Hz, 2H, Ar), 7.45-7.53 (m, 1H, Ar), 7.56 (s, 4H, Ar), 10.98 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 21.95, 22.36, 27.90, 31.18, 45.06, 51.58,54.00, 56.96, 65.32, 69.01, 115.00, 115.36, 127.79, 129.81, 129.95,130.78, 130.95, 133.34, 137.83, 153.33, 167.94, 169.95, 170.96, 172.83;LCMS MH=478; Anal. Calcd for C₂₆H₂₇N₃O₆ 0.95HCl+1.2H₂O: C, 58.51; H,5.73; N, 7.87; Cl, 6.31; Found: C, 58.57; H, 5.46; N, 7.89; Cl, 6.14.

5.443-[1-OXO-4-(4-[1,2,4]TRIAZOL-4-YLMETHYL-BENZYLOXY)-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Preparation of4-Carbamoyl-4-[1-oxo-4-(4-[1,2,4]triazol-4-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

To a solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.804 g, 1.691 mmol) in acetonitrile (20 ml) was added1H-1,2,4-triazole (0.350 g, 5.07 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.839 ml, 5.07 mmol) at roomtemperature. The mixture was stirred at room temperature for two daysand then diluted by methylene chloride (50 mL) and washed with saturatedsodium bicarbonate (10 mL) and brine (10 mL). The organic layer wasconcentrated and purified on silica gel column (MeOH/CH₂Cl₂ gradientfrom 1% to 9% in 50 min) to give4-Carbamoyl-4-[l-oxo-4-(4-[1,2,4]triazol-4-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as an oil (0.25 g, 32% yield); ¹H NMR (DMSO-d₆) δ1.98-2.33 (m, 4H, CHH, CHH, CHH, CHH), 3.50 (s, 3H, CH₃), 4.34-4.58 (m,2H, CH₂), 4.72 (dd, J=4.9, 10.4 Hz, 1H, NCH), 5.26 (d, J=17.9 Hz, 4H,CH₂, CH₂), 7.18 (br. s., 1H, NHH), 7.22-7.38 (m, 4H, Ar), 7.39-7.53 (m,3H, Ar), 7.58 (br. s., 1H, NHH), 8.62 (s, 2H, Ar). It was used in thenext step without further purification.

Step 2: Preparation of3-[1-Oxo-4-(4-[1,2,4]triazol-4-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione

To a stirred solution of methyl4-(4-(4-((4H-1,2,4-triazol-4-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(0.23 g, 0.496 mmol) in THF (15 ml) in an ice-bath was added potassium2-methylpropan-2-olate (0.134 g, 1.19 mmol). The mixture was stirred for10 minutes and 1N HCl (2 ml to pH=2) was added, then neutralized bysaturated sodium bicarbonate (3 ml to pH=7). Ethyl acetate (40 ml) wasadded to the mixture and stirred for five minutes. The organic phase wasseparated, washed with brine (10 ml), and evaporated to give a whitesolid, which was purified on silica gel column (MeOH/CH₂Cl₂ from 0% to10% in 30 min) to give3-[1-Oxo-4-(4-[1,2,4]triazol-4-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (58 mg, 27% yield); mp173-175° C.; HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 5.05min (95.2%); ¹H NMR (DMSO-d₆) δ 1.91-2.04 (m, 1H, CHH), 2.35-2.48 (m,1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.83-2.99 (m, 1H, CHH), 4.18-4.46 (m,2H, CH₂), 5.10 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 5.29(s, 2H, CH₂), 7.26-7.38 (m, 4H, Ar), 7.43-7.54 (m, 3H, Ar), 8.62 (s, 2H,2NH), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.35, 31.20, 45.08, 47.26,51.59, 69.13, 114.97, 115.29, 127.81, 128.18, 129.81, 129.97, 133.32,136.53, 143.22, 153.37, 167.98, 170.96, 172.83. LC/MS (M+1)⁺=432; AnalCalcd for C₂₃H₂₁N₅O₄C, 64.03; H, 4.91; N, 16.23; Found: C, 61.85; H,5.06; N, 14.92.

5.45 3-(4-((4-((2-METHYL-1H-IMIDAZOL-1-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To the suspension of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.5 g, 1.128 mmol) and 2-methyl-1H-imidazole (0.108 g, 1.315 mmol) inacetonitrile (5 mL) was added DIEA (0.22 ml, 1.260 mmol) at roomtemperature. The suspension was stirred at room temperature overnight.To the suspension was added water (15 mL). The suspension was stirred atroom temperature for 15 min. The suspension was filtered and washed withwater (3×10 mL) to give a solid. The solid purified with Prep HPLC(Xbridge C18, 10 μm, 50×250 mm, 143 mL/min, 240 nM, 2/98/2 min, gradientto 95/5 0.1% formic acid in CH₃CN/0.1% formic acid in H2O in 13 min),and desired factions were collected. The solvent was removed in vacuo togive an oil, To the oil was added EtOAc (20 mL) to give a solid and thesuspension was stirred at room temperature for 30 min. The suspensionwas filtered and washed with EtOAc (10 mL) and ether (10 mL) to give3-(4-((4-((2-methyl-1H-imidazol-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (43 mg, 8.6% yield): HPLC: (Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄): RT=3.18 min(99.4%); mp: 275-277° C.; ¹H NMR (DMSO-d₆) δ 1.86-2.07 (m, 1H, CHH),2.22 (s, 3H, CH₃), 2.33-2.49 (m, 1H, CHH), 2.52-2.63 (m, 1H, CHH),2.79-3.03 (m, 1H, CHH), 4.16-4.30 (m, 1H, CHH), 4.33-4.46 (m, 1H, CHH),5.10 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.15 (s, 2H, CH₂), 5.22 (s, 2H,CH₂), 6.76 (brs, 1H, Ar), 7.08-7.20 (m, 3H, Ar), 7.26-7.36 (m, 2H, Ar),7.43-7.52 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 12.70,22.31, 31.16, 45.04, 48.31, 51.53, 69.16, 114.93, 115.25, 120.23,126.46, 127.04, 128.06, 129.78, 129.95, 133.28, 135.88, 137.34, 153.39,167.97, 170.95, 172.81; LCMS: MH=445; Anal. Calcd for C₂₅H₂₄N₄O₄+0.3H₂O:C, 66.74; H, 5.51; N, 12.45; Found: C, 66.69; H, 5.24; N, 12.23.

5.463-{4-[4-(2,3-DIHYDRO-INDOL-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1 Preparation of4-[4-(4-Bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester

To a 1000 mL RBF were charged methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (9.76 g, 33.4mmol), 1,4-bis(bromomethyl)benzene (26.4 g, 100 mmol) and potassiumcarbonate (4.61 g, 33.4 mmol), was added 500 mL of CH₃CN. The mixturewas stirred at 50° C. for five hours and filtered, rinsed with CH₃CN (20ml). The filtrate was evaporated to give a white solid, which waspurified by silica gel column (MeOH/CH₂Cl₂) to give4-[4-(4-Bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as a white solid (13.4 g, 84% yield). ¹H NMR (DMSO-d₆)δ 1.97-2.13 (m, 1H, CHH), 2.13-2.35 (m, 3H, CH₂, CHH), 3.50 (s, 3H,CH₂), 4.32-4.63 (m, 2H, CH₂), 4.65-4.84 (m, 3H, CH₂, NCH), 5.25 (s, 2H,CH₂), 7.19 (s, 1H, NHH), 7.23-7.36 (m, 2H, Ar), 7.38-7.52 (m, 5H, Ar),7.58 (br. s., 1H, NHH).

Step 2: Preparation of4-Carbamoyl-4-{4-[4-(2,3-dihydro-indol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyric acid methyl ester

To the CH₃CN solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 1.052 mmol) was added indoline (0.142 ml, 1.262 mmol) and DIPEA(0.220 ml, 1.262 mmol). The mixture was stirred overnight. The mixturewas concentrated and extracted with water (15 mL) and EtOAc (20 mL). Theorganic layer was washed with NaHCO₃ (sat. 15 mL), brine (15 mL) andconcentrated on rota-vap to give4-Carbamoyl-4-{4-[4-(2,3-dihydro-indol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyric acid methyl ester a solid (0.5 g, 93%).It was used in the next step directly.

Step 3: Preparation of3-{4-[4-(1,3-Dihydro-isoindol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-1-isoindol-2-yl}-piperidine-2,6-dione

To the THF solution of methyl5-amino-4-(4-(4-(indolin-1-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 0.974 mmol) was added KOtBu (0.131 g, 1.168 mmol) at 0° C. Afterstirring at 0° C. for 15 min., the mixture was added 2 mL of 1N HClfollowed by 10 mL of sat. NaHCO₃ and 25 mL of EtOAc. The mixture wasseparated and the organic layer was washed with water (10 mL), brine (10mL) and concentrated. The resulted white solid was purified on silicagel column eluted with DCM and MeOH to give3-{4-[4-(1,3-Dihydro-isoindol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-1-isoindol-2-yl}-,piperidine-2,6-dione as white solid (200 mg, 43%). melting point:173-175° C. LC-MS m/e=482. HPLC Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂Oduring 5 min and stay at 95/5 for 5 min: 7.58 min (93%). ¹H NMR(DMSO-d₆) δ 1.90-2.04 (m, 1H, CHH), 2.33-2.47 (m, 1H, CHH), 2.56-2.65(m, 1H, CHH), 2.79-3.02 (m, 4H, CH₂, CHH), 3.13-3.30 (m, 2H, CH₂), 3.32(s, 3H, CH₂), 4.10-4.59 (m, 4H, CH₂, CH₂), 4.99-5.18 (m, 1H, NCH), 5.23(s, 2H, CH₂), 6.49-6.65 (m, 2H, Ar), 6.82-7.16 (m, 2H, Ar), 7.25-7.43(m, 4H, Ar), 7.42-7.62 (m, 3H, Ar), 10.96 (s, 1H, NH). ¹³C NMR (DMSO-d₆)δ 22.35, 27.92, 31.20, 45.09, 51.58, 52.15, 52.76, 69.39, 106.89,114.98, 115.24, 117.20, 124.24, 127.04, 127.85, 128.07, 129.47, 129.81,129.97, 133.31, 135.30, 138.16, 152.16, 153.48, 168.01, 170.96, 172.83.Anal Calcd for C₂₇H₂₉N₃O₄: C %: 72.33, H %: 5.65, N %: 8.73; Found: C %:72.14, H %: 5.51, N %: 8.47.

5.473-(4-((3-(MORPHOLINOMETHYL)-1,2,4-OXADIAZOL-5-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Sodium borohydride (179 mg, 4.72 mmol) was added to the solutionof ethyl 3-(chloromethyl)-1,2,4-oxadiazole-5-carboxylate (900 mg, 4.72mmol) in ethanol (10 mL) at 0° C. The mixture was stirred at 0° C. for 1hour, and then quenched with HCl (1N, 5 mL). The solvent was evaporated,the residue was partitioned between ethyl acetate (30 mL) and water (10mL), the organic layer was washed with brine, dried over magnesiumsulfat, and the solvent was evaporated to give 510 mg of(3-(chloromethyl)-1,2,4-oxadiazol-5-yl)methanol, the crude was used inthe next step without further purification.

Step 2: Polymer-supported triphenylphosphine (1.6 mmol/g, 3.16 g, 5.05mmol) was added to a stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (984 mg, 3.37mmol) in THF (30 mL) at 0° C., followed by diisopropyl azodicarboxylate(1.02 g, 5.05 mmol), after stirring for 10 minutes,(3-(chloromethyl)-1,2,4-oxadiazol-5-yl)methanol (500 mg, 3.37 mmol) wasadded, the mixture was stirred at room temperature overnight andfiltered. The resin was washed with ethyl acetate (10×20 mL). Thecombined filtrate was evaporated to dryness. The crude was purified byISCO (80 g column, MeOH/CH₂Cl₂ gradient from 0% to 5% in 40 min) to givemethyl5-amino-4-(4-((3-(chloromethyl)-1,2,4-oxadiazol-5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(480 mg, 34% yield). ¹H NMR (DMSO-d₆) δ 1.20 (d, J=7.0 Hz, 2H, CH₂),1.95-2.22 (m, 2H, CH₂), 3.50 (s, 3H, CH₃), 4.38-4.62 (m, 2H, CH₂), 4.73(d, J=5.7 Hz, 1H, CH), 4.94 (s, 2H, CH₂), 5.72 (s, 2H, CH₂), 7.21 (br.s., 1H, NHH), 7.32-7.41 (m, 2H, Ar), 7.49 (d, J=7.7 Hz, 1H, Ar), 7.61(br. s., 1H, NHH).

Step 3: To a solution of methyl5-amino-4-(4-((3-(chloromethyl)-1,2,4-oxadiazol-5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(460 mg, 1.088 mmol) in acetonitrile (10 mL) were added morpholine(0.114 mL, 1.306 mmol) and triethyl amine (0.182 mL, 1.306 mmol). Theformed mixture was stirred at room temperature overnight. The solventwas evaporated t dryness, the crude was partitioned between ethylacetate (50 mL) and water (10 mL) the organic layer was separated andwashed with brine, dried over magnesium sulfate. The solvent wasevaporated to give methyl5-amino-4-(4-((3-(morpholinomethyl)-1,2,4-oxadiazol-5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(410 mg, 80% yield). ¹H NMR (DMSO-d₆) δ 1.18 (d, J=5.3 Hz, 2H, CH₂),1.96-2.23 (m, 2H, CH₂), 2.42-2.50 (m, 4H, CH₂, CH₂), 3.50 (s, 3H, CH₃),3.53-3.62 (m, 4H, CH₂, CH₂), 3.68 (s, 2H, CH₂), 4.30-4.65 (m, 2H, CH₂),4.67-4.83 (m, 1H, CH), 5.68 (s, 2H, CH₂), 7.21 (br. s., 1H, NHH),7.28-7.42 (m, 2H, Ar), 7.48 (d, J=7.7 Hz, 1H, Ar), 7.61 (br. s., 1H,NHH).

Step 4: To a solution of methyl5-amino-4-(4-((3-(morpholinomethyl)-1,2,4-oxadiazol-5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(350 mg, 0.739 mmol) in THF was added was added potassium tert-butoxide(83 mg, 0.739 mmol) at 0° C. The mixture was stirred at 0° C. for 1hour, additional potassium tert-butoxide (20 mg, 0.27 mmol) was added,the mixture was stirred at room temperature for another 1 hour. Thereaction was quenched with acetic acid (1 mL), the solvent wasevaporated to dryness, the residue was partitioned between ethyl acetate(50 mL) and saturated sodium bicarbonate (10 mL). The organic layer wasseparated and washed with brine, dried over magnesium sulfate, thesolvent was evaporated under vacuo, the crude was purified by ISCO (40 gcolumn, MeOH/CH₂Cl₂ gradient from 0% to 5% in 40 min) to give3-(4-((3-(morpholinomethyl)-1,2,4-oxadiazol-5-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (230 mg, 70% yield). mp: 150-152° C.; ¹H NMR (DMSO-d₆)δ 1.90-2.08 (m, 1H, CHH), 2.31-2.44 (m, 1H, CHH), 2.44-2.49 (m, 4H, CH₂,CH₂), 2.53 (br. s., 1H, CHH), 2.79-3.05 (m, 1H, CHH), 3.48-3.63 (m, 4H,CH₂, CH₂), 3.69 (s, 2H, CH₂), 4.21-4.52 (m, 2H, CH₂), 5.12 (dd, J=5.0,13.3 Hz, 1H, CH), 5.69 (s, 2H, CH₂), 7.38 (dd, J=7.6, 11.0 Hz, 2H, Ar),7.47-7.66 (m, 1H, Ar); ¹³C NMR (DMSO-d₆) δ 22.28, 31.18, 45.00, 51.62,51.93, 52.58, 61.11, 65.95, 115.25, 116.41, 129.90, 130.00, 133.58,152.43, 166.98, 167.69, 170.92, 172.81, 174.88; HPLC: Waters XterraC-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80 CH₃CN/0.1% HCOONH₄t_(R)=4.65 (100%); Anal. Calcd for C₂₁H₂₃N₅O₆C, 57.14; H, 5.26; N,15.86; Found: C, 56.99; H, 4.95; N, 15.90.

5.483-{4-[3-(4-ISOPROPYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN solution (15 ml) of3-(4-(3-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.43 g, 0.970 mmol) was added 4-isopropylpiperidine (0.160 g, 1.261mmol) and N-ethyl-N-isopropylpropan-2-amine (0.321 ml, 1.940 mmol) atroom temperature. The cloudy mixture was stirred at room temperature for2 hours. The white suspension was evaporated under vacuum to get rid ofCH₃CN. The resulting white solid was stirred in water (50 ml) andextracted with methylene chloride (3×80 ml). The combined methylenechloride phases was washed by saturated sodium bicarbonate (2×50 ml),dried over sodium sulfate and concentrated to give as an off-white solid(72 mg, 50% yield); mp, 153-155° C. HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5 min,isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 4.74 min (96.3%). ¹H NMR(DMSO-d₆) δ 0.83 (d, J=6.8 Hz, 6H, 2CH₃), 0.89-1.02 (m, 1H, CH), 1.14(qd, J=3.9, 12.2 Hz, 2H, CH₂), 1.37 (dq, J=6.6, 13.2 Hz, 1H, CH), 1.55(dd, J=1.4, 10.9 Hz, 2H, CH₂), 1.75-1.91 (m, 2H, CH₂), 1.92-2.05 (m, 1H,CHH), 2.34-2.48 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.80 (d, J=11.5Hz, 2H, CH₂), 2.84-3.00 (m, 1H, CHH), 3.43 (s, 2H, CH₂), 4.20-4.47 (m,2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.25 (s, 2H, CH₂),7.20-7.28 (m, 1H, Ar), 7.28-7.41 (m, 5H, Ar), 7.43-7.53 (m, 1H, Ar),10.97 (s, 1H, NH). 13C NMR (DMSO-d₆) δ 19.68, 22.39, 28.89, 31.21,31.95, 41.85, 45.09, 51.59, 53.62, 62.25, 69.63, 115.17, 115.26, 126.13,127.87, 128.29, 129.78, 129.95, 133.31, 136.44, 139.01, 153.46, 167.99,170.95, 172.80. LC/MS (M+1)+=490; Anal Calcd for C₂₉H₃₅N₃O₄+0.2H₂O: C,70.62; H, 7.23; N, 8.52; Found: C, 70.41; H, 7.26; N, 8.44.

5.493-{1-OXO-4-[3-(4-PHENYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN solution (15 ml) of3-(4-(3-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.442 g, 0.997 mmol) was added 4-phenylpiperidine (0.209 g, 1.296 mmol)and N-ethyl-N-isopropylpropan-2-amine (0.330 ml, 1.994 mmol) at roomtemperature. The cloudy mixture was stirred at room temperatureovernight. The solvent was evaporated in vacuo to give an off-whitesolid, which was stirred in water (50 ml) and extracted with methylenechloride (3×50 ml). The combined methylene chloride phases were backwashed with water (50 ml), brine (50 ml), dried over sodium sulfate andevaporated to an off-white solid (˜0.5 g), which was stirred inacetonitrile (10 ml) at 50° C. oil bath for 10 minutes then filtered anddried ivcuum oven to give3-{1-Oxo-4-[3-(4-phenyl-piperidin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.36 g, 69% yield); mp, 226-228° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 4.79min, 96.0%. ¹H NMR (DMSO-d₆) δ 1.53-1.79 (m, 4H, 2CH₂), 1.89-2.11 (m,3H, CHH, CH₂), 2.33-2.47 (m, 2H, CHH, CHH), 2.53-2.62 (m, 1H, CHH),2.80-2.99 (m, 3H, CH₂, CHH), 3.51 (s, 2H, CH₂), 4.21-4.49 (m, 2H, CH₂),5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.27 (s, 2H, CH₂), 7.12-7.53 (m,12H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.36, 31.20, 33.05,41.81, 45.13, 51.59, 53.57, 62.23, 69.63, 115.19, 115.26, 125.94,126.24, 126.67, 128.04, 128.29, 128.45, 129.78, 129.97, 133.32, 136.49,138.82, 146.21, 153.46, 167.99, 170.95, 172.80. LC/MS (M+1)⁺=524; AnalCalcd for C₃₂H₃₃N₃O₄+0.3H₂O: C, 72.65; H, 6.40; N, 7.94; Found: C,72.48; H, 6.33; N, 7.78.

5.501-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYL}-1H-[1,2,3]TRIAZOLE-4-CARBOXYLIC ACID AMIDE

Step 1:4-[4-(4-Azidomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester

To the mixture of sodium azide (0.226 g, 3.47 mmol) in Ethanol (40 mL)at room temperature was added methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.5 g, 3.16 mmol). The resulting suspension was heated to reflux for 4hrs before it was cooled and added by water (50 mL) and EtOAc (200 mL).The mixture was extracted and the organic layer was washed with brine(50 mL). Organic layer was dried by MgSO₄ and concentrated under vacuoto give4-[4-(4-Azidomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as a yellow sticky solid (1.5 g, 109% crude yield)).The compound was used in the next step without further purification;LCMS MH=439.

Step 2: Propynoic acid amide

Ethyl propiolate (2 g, 20.39 mmol) was added to the stirred aqueousAMMONIA (5.99 g, 102 mmol) at −78° C. drop wise over 7 mins. Theresulting mixture was stirred under −78° C. for 1 hrs and was allowed toroom temperature. The reaction mixture was concentrated under high vacuoto give Propynoic acid amide as a yellow oil (1.41 g, 100% crude yield).The compound was used in the next step without further purification; ¹HNMR (DMSO-d₆) δ 4.07 (s, 1H, CH), 7.62 (br. s., 1H, NHH), 8.07 (br. s.,1H, NHH); ¹³C NMR (DMSO-d₆) δ 75.37, 78.51, 153.23.

Step 3:4-Carbamoyl-4-{4-[4-(4-carbamoyl-[1,2,3]triazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester

To a microwave vial was added methyl5-amino-4-(4-(4-(azidomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(300 mg, 0.69 mmol) and propiolamide (81 mg, 1.17 mmol) in Ethanol (2mL). The mixture was heated in microwave oven for 15 mins at 150° C. Thereaction mixture was concentrated and stirred in EtOAc (20 mL). Themixture was filtered to give4-Carbamoyl-4-{4-[4-(4-carbamoyl-[1,2,3]triazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a solid (255 mg, 73% crude yield); LCMS MH=507.

Step 4:1-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl)oxymethyl]-benzyl}-1H-[1,2,3]triazole-4-carboxylicacid amide

To the stirred suspension of methyl5-amino-4-(4-(4-((4-carbamoyl-1H-1,2,3-triazol-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(250 mg, 0.49 mmol) in Tetrahydrofuran (15 mL) at room temperature wasadded POTASSIUM TERT-BUTOXIDE (55.4 mg, 0.49 mmol). The resultingsuspension was stirred at room temperature for two hrs and kept infridge overnight. The reaction mixture was added by POTASSIUMTERT-BUTOXIDE (110 mg, 1.0 mmol) two portions and stirred at roomtemperature for 1 hr before it was diluted by EtOAc (30 mL). Thesuspension was added by HCl (aq, 1N, 4 mL) and filtered. The filtratewas extracted and the organic layer was dried by MgSO₄ and concentratedunder vacuo. The residue was purified by ISCO chromatography and theproduct was stirred in CH₃CN (5 mL). The mixture was filtered to give1-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-1H-[1,2,3]triazole-4-carboxylicacid amide. As a white solid (21 mg, 9% yield); HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 30/70, (CH₃CN/0.1% H₃PO₄), 3.5min (97.4%); mp: N/A; ¹H NMR (DMSO-d₆) δ 1.90-2.03 (m, 1H, CHH), 2.44(dd, J=4.3, 13.2 Hz, 1H, CHH), 2.54-2.63 (m, 1H, CHH), 2.82-2.98 (m, 1H,CHH), 4.24 (d, J=17.4 Hz, 1H, CHH), 4.40 (d, J=17.6 Hz, 1H, CHH), 5.10(dd, J=5.0, 13.3 Hz, 1H, CHH), 5.24 (s, 2H, CH₂), 5.66 (s, 2H, CH₂),7.25-7.41 (m, 4H, Ar), 7.42-7.57 (m, 4H, NHH, Ar), 7.85 (s, 1H, NHH),8.61 (s, 1H, triazole), 10.96 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.32,31.19, 45.07, 51.57, 52.75, 69.12, 114.94, 115.29, 126.66, 128.15,129.82, 129.97, 133.32, 135.45, 136.73, 143.12, 153.38, 161.39, 167.99,170.97, 172.83; LCMS MH=475; Anal. Calcd for C₂₄H₂₂N₆O₅: C, 60.75; H,4.67; N, 17.71; Found: N/A.

5.513-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYL}-3H-[1,2,3]TRIAZOLE-4-CARBOXYLIC ACID AMIDE

Step 1: 4-[4-(4-Azidomethyl-benzyloxy)-1-oxo-1,3-dihydroisoindol-2-yl]-4-carbamoyl-butyric acid methyl ester

To the mixture of sodium azide (0.226 g, 3.47 mmol) in Ethanol (40 mL)at room temperature was added methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.5 g, 3.16 mmol). The resulting suspension was heated to reflux for 4hrs before it was cooled and added by water (50 mL) and EtOAc (200 mL).The mixture was extracted and the organic layer was washed with brine(50 mL). Organic layer was dried by MgSO₄ and concentrated under vacuoto give4-[4-(4-Azidomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as a yellow sticky solid (1.5 g, 109% crude yield)).The compound was used in the next step without further purification;LCMS MH=439.

Step 2: Propynoic Acid Amide

Ethyl propiolate (2 g, 20.39 mmol) was added to the stirred aqueousAMMONIA (5.99 g, 102 mmol) at −78° C. drop wise over 7 mins. Theresulting mixture was stirred under −78° C. for 1 hrs and was allowed toroom temperature. The reaction mixture was concentrated under high vacuoto give Propynoic acid amide as a yellow oil (1.41 g, 100% crude yield).The compound was put to next step without further purification; ¹H NMR(DMSO-d₆) δ 4.07 (s, 1H, CH), 7.62 (br. s., 1H, NHH), 8.07 (br. s., 1H,NHH); ¹³C NMR (DMSO-d₆) 75.37, 78.51, 153.23.

Step 3:4-Carbamoyl-4-{4-[4-(5-carbamoyl-[1,2,3]triazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester

To a microwave vial was added methyl5-amino-4-(4-(4-(azidomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(300 mg, 0.686 mmol) and propiolamide (81 mg, 1.166 mmol) in Ethanol (2mL). The mixture was heated in microwave oven for 15 mins at 150° C. Thereaction mixture was concentrated and stirred in EtOAc (20 mL). Themixture was filtered and the filtrate was concentrated under vacuo andthe residue was purified by ISCO chromatography to give4-Carbamoyl-4-{4-[4-(5-carbamoyl-[1,2,3]triazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a solid (50 mg, 14% yield); LCMS MH=507.

Step 4:3-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-3H-[1,2,3]triazole-4-carboxylic acid amide

To the stirred solution of methyl5-amino-4-(4-(4-((5-carbamoyl-1H-1,2,3-triazol-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(50.0 mg, 0.099 mmol) in Tetrahydrofuran (10 mL) at room temperature wasadded potassium 2-methylpropan-2-olate (41.00 mg, 0.37 mmol). Thereaction mixture was stirred at room temperature for 2 hrs before it wasadded by EtOAc (15 mL) followed by the addition of HCl (1N, aq, 2 mL).The mixture was extracted arid the organic layer was washed with NaHCO₃(aq, sat., 5 mL) and brine (5 mL). The organic layer was dried by MgSO₄and concentrated under vacuo to give a white solid. The white solid wasstirred in CH₃CN (4 mL) and ether (15 mL). The mixture was filtered togive3-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-3H-[1,2,3]triazole-4-carboxylic acid amide as a whitesolid (40 mg, 85% yield); HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm,1 mL/min, 240 nm, 30/70, (CH₃CN/0.1% H₃PO₄), 3.88 min (95.7%); mp:280-282° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.03 (m, 1H, CHH), 2.34-2.48 (m,1H, CHH), 2.59 (br. s., 1H, CHH), 2.81-2.99 (m, 1H, CHH), 4.23 (d,J=17.6 Hz, 1H, NHH), 4.40 (d, J=17.6 Hz, 1H, CHH), 5.10 (dd, J=5.0, 13.1Hz, 1H, CHH), 5.21 (s, 2H, CH₂), 5.94 (s, 2H, CH₂), 7.24 (d, J=8.1 Hz,2H, M₀₁), 7.31 (dd, J=4.2, 7.6 Hz, 2H, Ar), 7.41-7.53 (m, 3H, Ar), 7.81(s, 1H, NHH), 8.23 (s, 1H, NHH), 8.26 (s, 1H, triazole), 10.96 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 22.30, 31.16, 45.04, 51.53, 51.65, 69.14,114.85, 115.25, 127.69, 127.98, 129.78, 129.93, 130.34, 133.28, 134.67,136.10, 136.27, 153.39, 158.90, 167.97, 170.93, 172.81; LCMS MH=475;Anal. Calcd for C₂₄H₂₂N₆O₅+0.5H₂O: C, 59.62; H, 4.80; N, 17.38; Found:C, 59.82; H, 4.65; N, 17.09.

5.52(R)-3-[4-(4-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: 3-Hydroxy-2-methyl-benzoic acid methyl ester

3-hydroxy-2-methylbenzoic acid (105 g, 690 mmol) was added to MeOH (800mL) in 2 L three neck RB flask equipped with condenser, thermometer andstirring bar followed by the addition of MeOH (250 ml). And H₂SO₄ (10mL, 180 mmol) was added to above solution. The reaction mixture wasstirred at 62° C. for 17 hrs before it was concentrated. The residue(200 mL) was added to water (600 mL) slowly at room temperature andwhite solid was formed. The suspension was stirred in ice bath for 30mins and filtered. The solid was washed by water (5×250 mL) and dried togive 3-Hydroxy-2-methyl-benzoic acid methyl ester as a white solid (100g, 87% yield). The compound was put to next step without furtherpurification: LCMS MH=167; ¹H NMR (DMSO-d₆) δ 2.28 (s, 3H, CH₃), 3.80(s, 3H, CH₃), 6.96-7.03 (m, 1H, Ar), 7.09 (t, J=7.8 Hz, 1H, Ar),7.14-7.24 (m, 1H, Ar), 9.71 (s, 1H, OH).

Step 2: 3-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-benzoic acid methylester

To a 1 L three neck RB flask equipped with stirring bar and thermometerwas added DMF (300 mL), methyl 3-hydroxy-2-methylbenzoate (90 g, 542mmol) and imidazole (92 g, 1354 mmol). TBDMS-Cl (90 g, 596 mmol) wasadded to above solution in portions to control the internal temp between15-19° C. over 20 mins and after addition the internal temp droppedbelow 10° C. The ice bath was removed and the reaction mixture wasstirred at room temperature for 16 hrs. The reaction mixture was addedto ice water (500 mL) and the resulting solution was divided to twoportions (700 ml×2). Each portion was extracted with EtOAc (700 mL). Andeach organic layer was washed with cold water (350 ml) and brine (350ml). Organic layers were combined and dried by MgSO4. Organic layer wasconcentrated to give 3-(tert-Butyl-dimethyl-silanyloxy)-2-methyl-benzoicacid methyl ester as a light brown oil (160 g, 100% crude yield). Thecompound was put to next step without further purification: LCMS MH=281;¹H NMR (DMSO-d₆) δ −0.21 (s, 6H, CH₃, CH₃), 0.73-0.84 (m, 9H, CH₃, CH₃,CH₃), 2.10 (s, 3H, CH₃), 3.60 (s, 3H, CH₃), 6.82 (dd, 1H, Ar), 6.97 (t,J=7.9 Hz, 1H, Ar), 7.13 (dd, J=1.1, 7.7 Hz, 1H, Ar)

Step 3: 2-Bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-benzoic acidmethyl ester

NBS (49.8 g, 280 mmol) was added to methyl 3-(tert-butyldimethylsilyloxy)-2-methylbenzoate (78.4 g, 280 mmol) in methyl acetate(500 mL) at room temperature to give an orange colored suspension. Theresulting reaction mixture was heated in oil bath to 40° C. and shinedby 300 wt sunlight bulb at reflux for 4 hrs. The reaction mixture wascooled down and washed by Na₂SO₃ solution 2×(600 mL, 50% saturatedconcentration), water (500 mL) and brine (600 mL). Organic layer wasdried by MgSO₄ and decolored by charcoal. Organic layer was concentratedto give 2-Bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-benzoic acidmethyl ester as a light brown oil (96 g, 91% crude yield). The compoundwas put to next step without further purification: LCMS M-Br=279; ¹H NMR(DMSO-d₆) δ 0.05-0.11 (m, 6H, CH₃, CH₃), 0.82 (s, 9H, CH₃, CH₃, CH₃),3.65 (s, 3H, CH₃), 4.74 (s, 2H, CH₂), 6.94 (dd, J=1.3, 8.1 Hz, 1H, Ar),7.10-7.20 (m, 1H, Ar), 7.21-7.29 (m, 1H, Ar); LCMS

Step 4: (R)4-[4-(tert-Butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid benzyl ester

To the stirred solution of methyl2-(bromomethyl)-3-(tert-butyldimethylsilyloxy)benzoate (15.32 g, 36.7mmol) in Acetonitrile (130 mL) was added (R)-benzyl4,5-diamino-5-oxopentanoate hydrochloride (10 g, 36.7 mmol) at roomtemperature. The resulting suspension was added by DIPEA (13.45 ml, 77mmol) through an addition funnel over 5 mins and the suspension becameclear solution. The reaction mixture was heated at 40° C. for 31 hrs androom temperature 18 hrs before it was concentrated under vacuo. Theresidue was stirred in diethyl ether (120 mL) and white solid wasformed. The mixture was filtered and solid was washed with diethyl ether(80 mL×4). Filtrates was washed with HCl (1N aq, 80 mL) and NaHCO₃ (aq.,sat., 80 mL) consecutively before it was concentrated under vacuo. Theresidue was purified by ISCO chromatography to give (R)4-[4-(tert-Butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid benzyl ester as a light yellow sticky solid (15.0 g, 101% crudeyield). The compound was put to next step without further purification;1H NMR (DMSO-d₆) δ 0.00 (s, 3H, CH₃), 0.01 (s, 3H, CH₃), 0.75 (s, 9H,CH₃, CH₃, CH₃), 1.73-2.16 (m, 4H, CH₂, CH₂), 4.03-4.35 (m, 2H, CHH,CHH), 4.53 (dd, J=5.1, 10.4 Hz, 1H, CHH), 4.64-4.82 (m, 2H, CH₂),6.77-6.89 (m, 1H, Ar), 6.97 (s, 1H, NHH), 7.01-7.23 (m, 7H, Ar), 7.37(s, 1H, NHH); LCMS MH=483.

Step 5: (R)4-Carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidbenzyl ester

To the stirred solution of (R)-benzyl5-amino-4-(4-(tert-butyldimethylsilyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(8.37 g, 17.3 mmol) in DMF (40 mL) and Water (4.4 mL) at ˜15° C. wasadded potassium carbonate (1.20 g, 8.7 mmol) in one portion. Theresulting light yellow suspension was stirred at room temperature for 1hr before it was added by acetonitrile (50 mL) followed by the additionof hydrogen chloride (aq, 12 N, 1.7 ml, 20.8 mmol) and white solid wasformed. The mixture was filtered and the filtrate was concentrated invacuo. The residue purified by ISCO to give (R)4-Carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidbenzyl ester as a glass like sticky solid (5.75 g, 90% yield). ¹H NMR(DMSO-d₆) δ 2.01-2.39 (m, 4H, CH₂, CH₂), 4.34 (d, J=17.4 Hz, 1H, CHH),4.49 (d, J=17.4 Hz, 1H, CHH), 4.75 (dd, J=5.0, 10.3 Hz, 1H, CHH), 4.96(d, J=12.5 Hz, 1H, CHH), 5.03 (d, J=12.5 Hz, 1H, CHH), 6.99 (d, J=7.7Hz, 1H, Ar), 7.10-7.24 (m, 2H, NHH, Ar), 7.25-7.41 (m, 6H, Ar), 7.58 (s,1H, NHH), 10.03 (s, 1H, OH); LCMS: MH=369.

Step 6: (R)4-[4-(4-Bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid benzyl ester

To the stirred solution of (R)-benzyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1 g, 2.71mmol) in Acetonitrile (35 mL) at room temperature was added1,4-bis(bromomethyl)benzene (2.15 g, 8.1 mmol) and POTASSIUM CARBONATE(0.375 g, 2.7 mmol). The resulting suspension was stirred at 50° C. for1 hr and room temperature overnight before it was filtered. The filtratewas concentrated and the residue was purified by ISCO to give (R)4-[4-(4-Bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid benzyl ester as a clear sticky solid (1.18 g, 78% yield); ¹H NMR(DMSO-d₆) δ 2.04-2.42 (m, 4H, CH₂, CH₂), 4.44 (d, J=17.8 Hz, 1H, CHH),4.55 (d, J=17.8 Hz, 1H, CHH), 4.68-4.80 (m, 3H, CHH, CH₂), 4.96 (d,J=12.5 Hz, 1H, CHH), 5.03 (d, J=12.5 Hz, 1H, CHH), 5.25 (s, 2H, CH₂),7.20 (s, 1H, NHH), 7.24-7.38 (m, 7H, Ar), 7.40-7.52 (m, 5H, Ar), 7.58(s, 1H, NHH); LCMS MH=551, 553

Step 7: (R)4-Carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid benzyl ester

To the solution of (R)-benzyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(395 mg, 0.716 mmol) in Acetonitrile (10 mL) was added MORPHOLINE (0.187ml, 2.1 mmol) at room temperature. The resulting solution was stirred atroom temperature for 2.5 hrs and the reaction was completed. Thereaction mixture was added by EtOAc (50 mL) and NaHCO₃ (sat. aq, 15 mL).The mixture was extracted and organic layer was dried by MgSO₄ andconcentrated down to give (R)4-Carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid benzyl ester as a sticky solid (350 mg, 88% crude yield). Theproduct was put to next step without further purification. ¹H NMR(DMSO-d₆) δ 2.01-2.40 (m, 8H, CH₂, CH₂, CH₂, CH₂), 3.46 (s, 2H, CH₂),3.56 (t, J=4.5 Hz, 4H, CH₂, CH₂), 4.42 (d, J=17.8 Hz, 1H, CHH), 4.54 (d,J=17.8 Hz, 1H, CHH), 4.75 (dd, J=5.0, 10.5 Hz, 1H, CHH), 4.95 (d, J=12.5Hz, 1H, CHH), 5.02 (d, J=12.5 Hz, 1H, CHH), 5.22 (s, 2H, CH₂), 7.19 (s,1H, NHH), 7.26-7.38 (m, 9H, Ar), 7.41-7.50 (m, 3H, Ar), 7.59 (s, 1H,NHH); LCMS MH=558.

Step 8:(R)-3-[4-(4-Morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione

To the stirred solution of (R)-benzyl5-amino-4-(4-(4-(morpholinomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(350 mg, 0.6 mmol) in Tetrahydrofuran (10 mL) at 0° C. was addedPOTASSIUM TERT-BUTOXIDE (70.4 mg, 0.6 mmol). The mixture was stirred at0° C. for 1 hr and KOtBu (10 mg) was added. And the reaction wascompleted in 1 more hour. The reaction mixture was diluted by EtOAc (40mL) and acidified by HCl (2 mL, 1N) and neutralized by NaHCO₃ (sat. aq,5 mL. The mixture was added by brine (10 mL) and extracted. Organiclayer was dried by MgSO₄ and concentrated under vacuo. The sticky whitesolid which was stirred in ether (40 mL) to give (R)3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (252 mg, 89% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 15/85, (CH₃CN/0.1% H₃PO₄), 5.41 min(99.7%); mp: 141-143° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.06 (m, 1H, CHH),2.25-2.47 (m, 5H, CHH, CH₂, CH₂), 2.53-2.65 (m, 1H, CHH), 2.81-3.02 (m,1H, CHH), 3.46 (s, 2H, CH₂), 3.50-3.62 (m, 4H, CH₂, CH₂), 4.25 (d,J=17.4 Hz, 1H, CHH), 4.41 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=4.9, 13.2Hz, 1H, CHH), 5.22 (s, 2H, CH₂), 7.33 (d, J=7.6 Hz, 4H, Ar), 7.39-7.54(m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 45.06,51.55, 53.11, 62.07, 66.14, 69.38, 114.94, 115.20, 127.61, 128.97,129.78, 129.93, 133.28, 135.27, 137.66, 153.48, 167.99, 170.96, 172.81;LCMS MH=450; Anal. Calcd for C₂₅H₂₇N₃O₅+0.3H₂O: C, 66.01; H, 6.12; N,9.24; Found: C, 66.00; H, 6.03; N, 9.12; Chiral HPLC Chiral AGP, 4×150mm, 5 μm, 0.8 mL, 240 nm, 5/95 iPOH/10 mM NH4OAc; R isomer=92% ee.

5.533-(4-((5-MORPHOLINOMETHYL)BENZO[D]THIAZOL-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: 2,3-Dichloro-5H-1,2,3dithiazolium chloride (6.7 g, 32.2 mmol)was added to a stirred solution of 2-bromo-5-methylaniline (6.0 g, 32.2mmol) in CH₂Cl₂ (130 mL) and stirred for 2 h. Pyridine (5.1 g, 64.5mmol) was added and mixture was stirred at room temperature for 2 h. Thereaction mixture was washed with water (2×40 mL), brine (40 mL) anddried. Solvent was removed and residue was stirred with ether (20 mL)and hexane (20 mL) to give(Z)-2-bromo-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-5-methylaniline(7.9 g, 76%): ¹H NMR (CDCl₃) δ 2.33 (s, 3H), 6.90=6.92 (m, 2H),7.53-7.56 (d, J=9 Hz, 1H).

Step 2: A mixture of(Z)-2-bromo-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-5-methylaniline(7.9 g, 24.6 mmol) and copper (I) iodide (5.2 g, 27.1 mmol) in pyridine(100 mL) was heated to reflux for 2 h. The reaction mixture was cooledand concentrated. Residue was dissolved in EtOAc (150 mL) and water (100mL). EtOAc layer was washed with water (3×50 mL), brine (50 mL) anddried. Solvent was removed and residue was purified by chromatography(SiO₂, 4/6 hecane/CH₂Cl₂ for 20 min then to 2/8 for 15 min) to give5-methylbenzo[d]thiazole-2-carbonitrile (3.1 g, 71%): ¹H NMR (CDCl₃) δ2.56 (s, 3H), 7.44-7.48 (dd, J=3 and 9 Hz, 1H), 7.84-7.87 (d, J=9 Hz,1H), 8.01 (s, 1H).

Step 3: A mixture of 5-methylbenzo[d]thiazole-2-carbonitrile (3.0 g,17.2 mmol) in methanol (100 mL) was cooled in ice bath. A solution ofsodium methoxide/methanol (25% wt, 13 mL) was added slowly and mixturewas stirred at room temperature for 1 h. The reaction mixture was cooledin ice bath and quenched with 6N HCl (15 mL). The mixture wasconcentrated and residue was dissolved in CH₂Cl₂ (100 mL) and washedwith water (2×35 mL), brine (35 mL) and dried. Solvent was removed andresidue was purified by chromatography (SiO₂, 2/8 hexane/CH₂Cl₂ for 15min then to CH₂Cl₂ over 10 min and hold for 10 min) to give methyl5-methylbenzo[d]thiazole-2-carboxylate (3.2 g, 88%): ¹H NMR (CDCl₃) δ2.54 (s, 3H), 4.08 (s, 3H), 7.36-7.39 (dd, J=3 and 9 Hz, 1H), 7.83-7.86(d, J=9 Hz, 1H), 8.02 (s, 1H).

Step 4: A mixture of methyl 5-methylbenzo[d]thiazole-2-carboxylate (3.1g, 15.1 mmol) and N-bromosuccinimide (3.0 g, 16.6 mmol) in methylacetate (50 mL) was heated at 60° C. oil bath with a 300 W bulb shiningto reaction mixture for 3 h. The Reaction mixture was cooled to roomtemperature and diluted with EtOAc (50 mL). The mixture was washed withwater (2×40 mL), brine (40 mL) and dried. Solvent was removed andresidue was purified by chromatography (SiO₂, 2/8 CH₂Cl₂/hexane for 15min then to CH₂Cl₂ for 15 min) to givemethyl5-(bromomethyl)benzo[d]thiazole-2-carboxylate (2.8 g, 65%): 1H NMR(CDCl₃) δ 4.09 (s, 3H), 4.66 (s, 2H), 7.59-7.62 (dd, J=3 and 9 Hz, 1H),7.95-7.98 (d, J=9 Hz, 1H), 8.22-8.23 (d, J=3 Hz, 1H).

Step 5: A solution of methyl5-(bromomethyl)benzo[d]thiazole-2-carboxylate (2.8 g, 9.8 mmol) inacetone (30 mL) was added slowly to a stirred suspension of morpholine(1.3 g, 14.7 mmol) and potassium carbonate (4.7 g, 34.2 mmol) andcatalytic amount of 18-crown-6 in acetone (20 mL) at 60° C. oil bath.The reaction mixture was stirred at 60° C. oil bath for 3 h then cooledand filtered. Filtrate was concentrated and residue was dissolved inEtOAc (100 mL) and washed with water (2×40 mL), brine (40 mL) and dried.Solvent was removed and residue was purified by chromatography (SiO₂,CH₂Cl₂ for 10 min then to 3% CH₃OH/CH₂Cl₂ over 5 min and hold for 15 minthen to 5% over 5 min and hold for 20 min) to give methyl5-(morpholinomethyl)benzo[d]thiazole-2-carboxylate (2.3 g, 80%): ¹H NMR(CDCl₃) δ 2.47-2.50 (m, 4H), 3.67-3.73 (m, 6H), 4.09 (s, 3H), 7.57-7.60(dd, J=3 and 9 Hz, 1H), 7.91-7.94 (d, J=9 Hz, 1H), 8.19 (s, 1H).

Step 6: A solution of methyl5-(morpholinomethyl)benzo[d]thiazole-2-carboxylate (2.2 g, 2.5 mmol) inTHF (50 mL) was added slowly to a stirred solution of LiAlH (t-BuO)₃/THF(1M, 15.3 mL, 15.3 mmol) in THF (20 mL) and reaction mixture was stirredat room temperature for 1 h. The reaction mixture was cooled andquenched with water (20 mL) cautionsly. The mixture was diluted withEtOAc (150 mL) and water (35 mL). The organic layer was washed withwater (40 mL), brine (40 mL) and dried. Solvent was removed and residuewas purified by chromatography (SiO₂, CH₂Cl₂ for 10 min then to 3%CH₃OH/CH₂Cl₂ over 5 min and hold for 15 min then to 5% over 5 min andhold for 20 min) to give(5-(morpholinomethyl)benzo[d]thiazol-2-yl)methanol (1.8 g, 90%): ¹H NMR(CDCl₃) δ 2.46-2.49 (m, 4H), 3.63 (s, 2H), 3.71-3.73 (m, 4H), 3.94 (b,1H), 5.04 (s, 2H), 7.37-7.41 (dd, J=3 and 9 Hz, 1H), 7.81-7.83 (d, J=9Hz, 1H), 7.91 (s, 1H); ¹³C NMR (CDCl₃) 553.56, 62.56, 63.16, 66.98,121.55, 123.14, 126.38, 133.51, 136.31, 153.13, 173.12.

Step 7: A suspension mixture of triphenylphosphine-polymer bound (4.1 g,4.9 mmol) in THF (40 mL) was cooled to 3° C. Diisopropylazodicarboxylate (0.9 g, 4.6 mmol) was added slowly at 3-5° C. Afterstirred at 3° C. for 10 min, a solution ofmethyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0 g,3.4 mmol) and (5-(morpholinomethyl)benzo[d]thiazol-2-yl)methanol (11 g,4.1 mmol) in THF (60 mL) was added slowly at 3-8° C. The reactionmixture was stirred at 3° C. for 10 in then warmed to room temperatureand stirred overnight. The reaction mixture was filtered and filtratewas concentrated. Residue was dissolved in CH₂Cl₂ (80 mL) and washedwith sat. NaHCO₃ (30 mL), water (30 mL), brine (30 mL) and dried.Solvent was removed and residue was purified by chromatography (SiO₂,CH₂Cl₂ for 10 min then to 3% CH₃OH/CH₂Cl₂ over 5 min and hold for 15 minthen to 5% over 5 min and hold for 20 min) to give methyl5-amino-4-(4-((5-(morpholinomethyl)benzo[d]thiazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.95 g, 52%); ¹H NMR (CDCl₃) δ 2.23 (m, 1H), 2.35-2.50 (m, 7H),3.64-3.74 (m, 6H), 4.46-4.52 (d, J=18 Hz, 1H), 4.57-4.63 (d, J=18 Hz,1H), 4.92-4.95 (1H), 5.30 (s, 3H), 5.58 (s, 2H), 5.65 (b, 1 HO, 6.53 (b,1H), 7.11-7.14 (d, J=9 Hz, 1H), 7.40-7.48 (m, 2H), 7.81-7.87 (m, 2H),7.99 (s, 1H).

Step 8: Potassium tert-butoxide/THF (1M, 1.7 mL, 1.7 mmol) was addedslowly to a stirred solution of methyl5-amino-4-(4-((5-(morpholinomethyl)benzo[d]thiazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.9 g, 1.7 mmol) in THF (25 mL) at 5° C. The reaction mixture wasstirred at 5° C. for 1 h then quenched with sat. NH₄Cl (5 mL). Themixture was diluted with CH₂C₂ (50 mL) and water (15 mL). Aq. layer wasextracted with CH₂Cl₂ (30 mL) and combined CH₂Cl₂ solution was washedwith brine (40 mL) and dried. Solvent was removed and residue wasrecrystallized from acetone to give3-(4-((5-(morpholinomethyl)benzo[d]thiazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.4 g, 55%): mp 228-230° C.; ¹H NMR (DMSO-d₆₎ δ 2.00-2.04 (m, 1H),2.37-2.63 (m, 6H), 2.88-2.94 (m, 1H), 3.56-3.62 (m, 6H), 4.32-4.38 (d,J=18 Hz, 1H), 4.47-4.53 (d, J=18 Hz, 1H), 5.11-5.17 (dd, J=3 and 12 Hz,1H), 5.75 (s, 2H), 7.38-7.52 (m, 4H), 7.94 (s, 1H), 8.04-8.07 (d, J=9Hz, 1H), 11.00 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.33, 31.18, 45.00, 51.63,53.08, 62.00, 66.17, 67.41, 115.29, 116.12, 122.00, 122.74, 126.50,129.96, 132.95, 133.52, 136.61, 152.60, 152.68, 167.80, 168.03, 170.96,172.83; Calcd for C₂₆H₂₆N₄O₅S+0.35H₂O: C, 60.89; H, 5.25; N, 10.92; S,6.25; Found: C, 60.59; H, 5.11; N, 10.85; S, 6.30.

5.54 3-(4-((4-((4,5-DIMETHYL-1H-IMIDAZOL-1-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a mixture of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.40 g, 0.90 mmol) and 4,5-dimethyl-1H-imidazole (0.24 g, 2.49 mmol) inacetonitrile (10 mL) was added N,N-diisopropylethyl amine (0.16 ml, 0.90mmol) at room temperature. The solution was stirred at room temperaturefor 24 h. To the suspension was added 0.2 M Phosphate Buffer pH 7.4 (50mL) to give a suspension. To the suspension was added EtOAc (30 mL) andthe suspension was stirred for 10 min. Part of solvent was removed togive a suspension. The suspension was filtered and washed with water togive a solid. The solid was purified with Prep HPLC (Xbridge C18, 10 μm,50×250 mm, 143 mL/min, 240 nM, 2/98/2 min, gradient to 98/2 CH₃CN 0.1%formic acid/H₂O 0.1% formic acid in 13 min) to give an oil. To the oilwas added ether (10 mL) and EtOAc (10 mL) to give a suspension. Thesuspension was filtered and washed with ether (10 mL) to give3-(4-((4-((4,5-dimethyl-1H-imidazol-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (110 mg, 27% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 5./95 gradient to 95/5 in 5 min CH₃CN/0.1%H₃PO₄, 4.91 (97.5%); mp: 180-182° C.; ¹H NMR (DMSO-d₆) δ 1.87-2.09 (m,7H, CHH, CH₃, CH₃), 2.31-2.48 (m, 1H, CHH), 2.52-2.65 (m, 1H, CHH),2.81-3.02 (m, 1H, CHH), 4.14-4.30 (m, J=17.6 Hz, 1H, CHH), 4.40 (d,J=17.6 Hz, 1H, CHH), 5.01-5.17 (m, 3H, CH₂, NCH), 5.22 (s, 2H, CH₂),7.12 (d, J=8.1 Hz, 2H, Ar), 7.25-7.38 (m, 2H, Ar), 7.41-7.54 (m, 3H,Ar), 7.56 (s, 1H, Ar), 10.97 (s, 1H, NH); 3C NMR (DMSO-d₆) δ 8.05,12.67, 22.31, 31.16, 45.03, 47.19, 51.53, 69.17, 114.93, 115.25, 121.69,126.87, 128.04, 129.78, 129.95, 132.92, 133.28, 135.54, 135.79, 137.53,153.39, 167.97, 170.95, 172.81; LCMS MH=459; Anal. Calcd forC₂₆H₂₆N₄O₄+0.5H₂O: C, 66.80; H, 5.82; N, 11.98; Found: C, 66.81; H,5.66; N, 11.91.

5.553-(4-((3-(MORPHOLINOMETHYL)ISOXAZOL-5-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: (3-((Tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-5-yl)methanol

A solution of ethyl3-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazole-5-carboxylate (3.7 g,14.49 mmol) in THF (100 mL) was cooled to 0° C., and then a 1M solutionof DIBALH in toluene (43.5 mL) was added dropwise over 30 min, and thenthe mixture was stirred at room temperature for 16 h. The mixture wasquenched a 1M aqueous solution of sodium potassium tartrate (100 mL) andwas then extracted with EtOAc (3×100 mL). The combined organic layerswere washed with water (150 mL) and brine (150 mL), dried (MgSO₄) andevaporated, providing 2.5 g of the product as an orange oil, in 81%yield; ¹H NMR (CDCl₃) δ 1.56-1.86 (m, 6H), 2.31 (br, 1H), 3.50-3.61 (m,1H), 3.83-3.95 (m, 1H), 4.61 (d, J=12.8 Hz, 1H), 4.68-4.83 (m, 4H), 6.32(s, 1H).

Step 2: (4 S)-Methyl5-amino-5-oxo-4-(1-oxo-4-((3-((tetrahydro-2H-pyran-2-yloxy)methyl)-isoxazol-5-yl)methoxy)isoindolin-2-yl)pentanoate

A mixture of (S)-methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-4-methyl-5-oxopentanoate (3.4g, 11.7 mmol),(3-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-5-yl)methanol (2.5 g,11.7 mmol), and triphenylphosphine, polymer-bound, 3 mmol/g (7.8 g, 23mmol) in THF (200 mL) was cooled to 0° C., and DIAD (4.6 ml, 23.5 mmol)was added. After 60 min, the ice bath was removed, and the mixture wasstirred for 16 h at ambient temperature. Then, the mixture was filteredand the filtrate was evaporated. The residue was chromatographed inmethylene chloride-methanol gradient. The product eluted at 2% MeOH, 3.4g, in 60% yield; ¹H NMR (CDCl₃) δ 1.51-1.87 (m, 6H), 2.09-2.51 (m, 4H),3.46-3.60 (m, 1H), 3.64 (s, 3H), 3.81-3.94 (m, 1H), 4.31-4.57 (m, 2H),4.59-4.66 (m, 1H), 4.67-4.85 (m, 2H), 4.87-4.98 (m, 1H), 5.12-5.32 (m,2H), 5.52 (br. s., 1H), 6.30-6.53 (m, 2H), 7.08 (d, J=7.6 Hz, 1H),7.35-7.52 (m, 2H).

Step 3:3-(4-((3-(Hydroxymethyl)isoxazol-5-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A solution of (4S)-methyl5-amino-5-oxo-4-(1-oxo-4-((3-((tetrahydro-2H-pyran-2-yloxy)methyl)isoxazol-5-yl)methoxy)isoindolin-2-yl)pentanoate(2.75 g, 5.64 mmol) was cooled to 0° C., and potassium tert-butoxide(0.633 g, 5.64 mmol) was added. After 30 min, AcOH (100 mL) and water(25 mL) were added, and the mixture was heated to 45° C. The mixturestirred at this temperature for 24 h, and was then evaporated undervacuum. A portion of the dried intermediate (1.86 g, 5.0 mmol) wasdissolved in acetonitrile (100 mL) and treated with methanesulfonylchloride (0.389 ml, 5.00 mmol) and TEA (0.730 ml, 5.25 mmol). After 2hrs stirring at room temperature methanesulfonyl chloride (0.438 ml,5.64 mmol) and TEA (0.823 ml, 5.92 mmol) were again added. After anadditional 1 h, the mixture was quenched with AcOH (1 mL) and evaporatedunder vacuum. The residue was partitioned between EtOAc (100 mL) andsaturated aqueous NaHCO₃ (100 mL), and the aqueous layer was extractedwith EtOAc (50 mL). The combined organic phases were washed withsaturated aqueous NaHCO₃ (100 mL), water (100 mL), and dried (MgSO₄).The mixture was evaporated and chromatographed using a methylenechloride-methanol gradient. The product eluted at −2% MeOH. The yieldafter drying was 1.6 g (71%); ¹H NMR (DMSO-d₆) δ 1.93-2.05 (m, 1H),2.35-2.48 (m, 1H), 2.55-2.63 (m, 1H), 2.83-3.00 (m, 1H), 3.33 (s, 3H),4.19-4.30 (m, 1H), 4.35-4.48 (m, 1H), 5.11 (dd, J=4.9, 13.2 Hz, 1H),5.38 (s, 2H), 5.49 (s, 2H), 6.84 (s, 1H), 7.40 (t, J=8.0 Hz, 2H),7.48-7.57 (m, 1H).

Step 4:3-(4-((3-(morpholinomethyl)isoxazol-5-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A mixture of(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)isoxazol-3-yl)methylmethanesulfonate (0.5 g, 1.113 mmol) in acetonitrile (10 mL) was cooledto 0° C. Morpholine (0.116 ml, 1.335 mmol) and DIEA (0.252 ml, 1.446mmol) were added, and the mixture stirred at that temperature. After 16h, the resultant suspension was filtered, and the solid was dried undervacuum. The product was obtained as a white solid, 0.4 g in 82% yield;mp 228-230° C. HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min,240 nm, 10/90 gradient to 90/10 CH₃CN/0.1% H₃PO₄ in 10 min: 4.38(99.82%). ¹H NMR (DMSO-d₆) δ 1.82-2.12 (m, 1H), 2.22-2.48 (m, 5H),2.54-2.67 (m, 1H), 2.79-3.05 (m, 1H), 3.55 (br., 6H), 4.16-4.49 (m, 2H),5.11 (dd, J=4.9, 13.2 Hz, 1H), 5.43 (s, 2H), 6.64 (s, 1H), 7.32-7.46 (m,2H), 7.46-7.61 (m, 1H), 10.98 (s, 1H). ¹³C NMR (DMSO-d₆) δ 22.30, 31.16,45.00, 51.58, 52.51, 52.87, 60.67, 65.98, 104.55, 115.09, 115.96,129.84, 129.96, 133.49, 152.63, 167.26, 167.80, 170.92, 172.81Anal.Calcd for C₂₂H₂₄N₄O₆: C, 59.99%; H, 5.49%; N, 12.72%; Found: C, 59.69%;H, 5.43%; N, 12.66%.

5.563-{4-[4-(4-TERT-BUTYL-[1,2,3]TRIAZOL-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1:4-[4-(4-Azidomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester

To the mixture of sodium azide (0.226 g, 3.47 mmol) in Ethanol (40 mL)at room temperature was added methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.5 g, 3.16 mmol). The resulting suspension was heated to reflux for 4hrs before it was cooled and added by water (50 mL) and EtOAc (200 mL).The mixture was extracted and the organic layer was washed with brine(50 mL). Organic layer was dried by MgSO₄ and concentrated under vacuoto give4-[4-(4-Azidomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as a yellow sticky solid (1.5 g, 109% crude yield)).The compound was used in the next step without further purification;LCMS MH=439.

Step 2:4-{4-[4-(4-tert-Butyl-[1,2,3]triazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester

3,3-dimethylbut-1-yne (752 mg, 9.2 mmol), methyl5-amino-4-(4-(4-(azidomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(400 mg, 0.9 mmol) and Toluene (4 mL) were sealed in a microwave vialand heated in a microwave oven at 125° C. for 3 hrs. The reactionmixture was concentrated and the residue was purified by ISCO give4-{4-[4-(4-tert-Butyl-[1,2,3]triazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester as a light glass like solid (160 mg, 34% yield). Thecompound was used in the next step without further purification; LCMSMH=520.

Step 3:3-{4-[4-(4-tert-Butyl-[1,2,3]triazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred solution of methyl5-amino-4-(4-(4-((4-tert-butyl-1H-1,2,3-triazol-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(160 mg, 0.3 mmol) in Tetrahydrofuran (5 mL) at 0° C. was addedpotassium tert-butoxide (34.6 mg, 0.3 mmol). The resulting solution wasstirred at 0° C. for 10 mins and the reaction was completed. Thereaction mixture was diluted by EtOAC (30 mL) and then acidified by HCl(1N, aq, 2 mL). The resulting mixture was added by NaHCO₃ (aq., sat., 2mL) and brine (5 mL). The mixture was extracted and organic layer wasdried by MgSO₄ and concentrated. The residue was purified by ISCO andprepHPLC to give3-{4-[4-(4-tert-Butyl-[1,2,3]triazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (15 mg, 10% yield). HPLC: Waters Symmetry C-18, 3.9×150mm, 5 m, 1 mL/min, 240 nm, 45/55, (CH₃CN/0.1% H₃PO₄), 3.67 min (97.5%);mp: N/A; ¹H NMR (DMSO-d₆) δ 1.26 (s, 9H, CH₃, CH₃, CH₃), 1.86-2.04 (m,1H, CHH), 2.33-2.45 (m, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.79-3.02 (m,1H, CHH), 4.24 (d, J=17.6 Hz, 1H, CHH), 4.41 (d, J=17.6 Hz, 1H, CHH),5.10 (dd, J=5.0, 13.1 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 5.53 (s, 2H,CH₂), 7.24-7.40 (m, 4H, Ar), 7.41-7.56 (m, 3H, Ar), 7.92 (s, 1H,triazole H), 10.96 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.31, 30.24, 31.16,45.06, 51.55, 52.33, 69.12, 114.88, 115.25, 119.84, 128.04, 129.78,129.93, 133.30, 136.01, 136.45, 153.38, 156.50, 167.96, 170.95, 172.81;LCMS MH=488.

5.57 3-(1-OXO-4-((4-((2,4,5-TRIMETHYL-1H-IMIDAZOL-1-YL) METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE FORMATE

Step 1: 2,4,5-Trimethyl-1H-imidazole

Acetaldehyde (0.32 ml, 5.8 mmol) was added to the mixture of biacetyl(0.51 ml, 5.8 mmol), ammonium acetate (4.03 g, 52.3 mmol) and AceticAcid (8 mL) in a microwave vial (20 mL). The vial was sealed and put onmicrowave oven for 5 mins at 180° C. The reaction mixture was added tomixture of ice and NH₄OH aq (30 mL) slowly and the resulting brownsolution was diluted by water (50 mL) and the mixture was extracted withEtOAC (3×35 mL). Organic layer was dried by MgSO₄ and concentrated undervacuo to give 2,4,5-Trimethyl-1H-imidazole as a brown oil (460 mg, 77%crude yield). The compound was put to next step without furtherpurification; ¹H NMR (DMSO-d₆) δ 1.75 (s, 3H, CH₃), 1.96 (s, 3H, CH₃),2.12 (s, 3H, CH₃), 11.10 (br. s., 1H, NH).

Step 2:3-(1-oxo-4-((4-((2,4,5-trimethyl-1H-imidazol-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione formate

To the stirred solution of 2,4,5-trimethyl-1H-imidazole (447 mg, 4.1mmol) in Acetonitrile (8 mL) was added3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(400 mg, 0.9 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.482 ml, 2.7mmol). The resulting solution was stirred at room temperature 18 hrsbefore it was added by EtOAC (70 mL) and NaHCO₃ (aq, sat, 25 mL). Somesolid was formed and filtered. The filtrate was extracted and organiclayer was concentrated. The residue combined with the solid was purifiedby PrepHPLC to give a light brown solid which was further purified by bestirred in CH₃CN (4 mL) and diethyl ether (30 mL) to give3-(1-oxo-4-((4-((2,4,5-trimethyl-1H-imidazol-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione formate as an off white solid (93 mg, 20% yield).HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80,(CH₃CN/0.1% H₃PO₄), 6.09 min (99.8%); 254-256° C.; ¹H NMR (DMSO-d₆) δ1.98 (d, J=9.1 Hz, 7H, CHH, CH₃, CH₃), 2.18 (s, 3H, CH₃), 2.34-2.47 (m,1H, CHH), 2.60 (br. s., 1H, CHH), 2.82-3.00 (m, 1H, CHH), 4.24 (d,J=17.6 Hz, 1H, CHH), 4.40 (d, J=17.6 Hz, 1H, CHH), 4.99-5.16 (m, 3H,CHH, CH₂), 5.22 (s, 2H, CH₂), 7.00 (d, J=8.1 Hz, 2H, Ar), 7.25-7.38 (m,2H, Ar), 7.46 (d, J=8.3 Hz, 3H, Ar), 8.20 (s, 1H, HCOOH), 10.97 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 12.31, 12.78, 22.33, 31.16, 45.03, 45.89,51.53, 69.16, 114.91, 115.23, 121.53, 126.10, 128.11, 129.78, 129.93,130.18, 133.28, 135.60, 137.32, 141.81, 153.41, 163.55, 167.97, 170.95,172.81; LCMS MH=473; Anal. Calcd for C₂₇H₂₈N₄O₄.HCOOH+1H₂O:C, 62.68; H,6.01; N, 10.44; Found: C, 62.54; H, 5.63; N, 10.35.

5.583-(4-((5-METHYL-1,3,4-OXADIAZOL-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: To a solution of 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (500mg, 3.77 mmol) in DMF (10 mL) were added methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1103 mg,3.77 mmol) and K₂CO₃ (573 mg, 4.15 mmol), the formed mixture was stirredat room temperature overnight. The solvent was evaporated under vacuum,the residue was partitioned between water (10 mL) and ethyl acetate (100mL), the organic layer was washed with saturated sodium carbonate (10mL), brine, dried over magnisium sulfate, and the solvent was evaporatedto dryness. The residue was purified by ISCO (80 g column, MeOH/CH₂Cl₂gradient from 0% to 5% in 50 min) to give methyl5-amino-4-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(860 mg, 59% yield); ¹H NMR (DMSO-d₆) δ 2.25 (d, J=6.8 Hz, 4H, CH₂,CH₂), 2.53 (s, 3H, CH₃), 3.49 (s, 3H, CH₃), 4.29-4.61 (m, 2H, CH₂),4.68-4.80 (m, 1H, CH), 5.52 (s, 2H, CH₂), 7.20 (s, 1H, NHH), 7.31-7.45(m, 2H, Ar), 7.49 (d, J=7.7 Hz, 1H, Ar), 7.59 (s, 1H, NHH)

Step 2: To a mixture of methyl5-amino-4-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(422 mg, 1.087 mmol) in THF (20 mL) was added potassium tert-butoxide(146 mg, 1.304 mmol) at 0° C. The formed mixture was warmed to roomtemperature and stirred at room temperature for 2 hours. The reactionwas quenched with aqueous HCl (1N, 1.5 mL), the solvent was evaporated,the residue was partitioned between saturated aqueous sodium bicarbonate(10 mL) and ethyl acetate (50 mL). The organic layer was washed withbrine, dried over magnesium sulfate. The solvent was evaporated undervacuum and the crude was reslurried with acetonitrile (5 mL) andfiltered to give3-(4-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(250 mg, 33% yield). mp: 206-208° C.; ¹H NMR (DMSO-d₆) δ 1.99 (s, 1H,CHH), 2.34-2.48 (m, 1H, CHH), 2.53 (s, 3H, CH₃), 2.55-2.68 (m, 1H, CHH),2.79-3.04 (m, 1H, CHH), 4.17-4.49 (m, 2H, CH₂), 5.11 (dd, J=5.0, 13.3Hz, 1H, CH), 5.53 (s, 2H, CH₂), 7.33-7.48 (m, 2H, Ar), 7.49-7.61 (m, 1H,Ar), 10.98 (br. s., 1H, NH); ¹³C NMR (DMSO-d₆) δ 10.46, 22.30, 31.16,44.96, 51.59, 59.78, 115.29, 116.30, 129.90, 129.97, 133.53, 152.47,162.12, 164.82, 167.71, 170.93, 172.80; HPLC: Waters Xterra C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80 CH₃CN/0.1% HCOONH₄ t_(R)=3.08(100%); Anal. Calcd for C₁₇H₁₆N₄O₅+0.2H₂O C, 56.73; H, 4.59; N, 15.57;Found: C, 56.88; H, 4.52; N, 15.31.

5.593-{4-[4-(1,3-DIHYDRO-ISOINDOL-2-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the THF solution of methyl5-amino-4-(4-(4-(isoindolin-2-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 0.974 mmol) was added potassium tert-butoxide (0.131 g, 1.168mmol) at 0° C. The mixture was stirred for 30 min and was added 2 mL of1N HCl followed by 10 mL of sat. NaHCO₃ and 25 mL of EtOAc. The mixturewas extracted and the organic layer was concentrated and the resultedsolid was purified on silica gel column eluted with DCM and MeOH to givea solid. The solid was recrystallized from 2 mL of CH₃CN to give3-{4-[4-(1,3-dihydro-isoindol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-1-isoindol-2-yl}-piperidine-2,6-dione(60 mg, 0.13%). m.p.: 153-155° C. LC-MS m/e=482. HPLC Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient 5/95 to 5/95CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stay at 95/5 for 5 min: 4.99min (95%); ¹H NMR (DMSO-d₆) δ 1.89-2.04 (m, 1H, CHH), 2.35-2.45 (m, 1H,CHH), 2.54-2.64 (m, 1H, CHH), 2.82-3.00 (m, 1H, CHH), 3.83 (s, 4H, CH₂,CH₂), 3.87 (s, 2H, CH₂), 4.19-4.50 (m, 2H, CH₂), 5.11 (dd, J=5.0, 13.1Hz, 1H, NCH), 5.25 (s, 2H, CH₂), 7.10-7.25 (m, 4H, Ar), 7.27-7.54 (m,8H, Ar), 10.97 (s, 1H, NH). ¹³CNMR (DMSO): δ 22.32, 31.17, 45.08, 49.30,51.54, 58.16, 69.32, 114.89, 115.24, 122.29, 122.84, 123.50, 127.78,127.82, 127.89, 129.94, 131.38, 133.50, 136.30, 137.50, 170.96, 172.82.Anal Calcd for C₂₉H₂₇N₃O₄: C % 72.33, H % 5.65, N % 8.73; Found: C %70.89, H % 5.31, N % 8.37.

5.603-{4-[4-(4-TERT-BUTYL-IMIDAZOL-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: 5-tert-Butyl-1H-imidazole

1-bromo-3,3-dimethylbutan-2-one (2.0 g, 11.2 mmol) and formamide (1.11g, 24.6 mmol) were mixed microwave vial and heated at 147° C. in thesealed tube for 5.5 hrs. The reaction mixture was cooled down anddiluted by water (40 mL). The mixture was extracted with hepatane (50mL). Aq layer was added by K₂CO₃ (10% wt aq, ˜25 mL) to pH 10. Theresulting solution was extracted with DCM (3×50 mL). Organic layer wasdried by MgSO₄ and concentrated to give 5-tert-Butyl-1H-imidazole as asticky yellow oil (560 mg, 40% yield). The compound was used in the nextstep without further purification; ¹H NMR (DMSO-d₆) δ 1.21 (s, 9H, CH₃,CH₃, CH₃), 6.66 (s, 1H, Ar), 7.47 (d, J=0.9 Hz, 1H, Ar), 11.70 (br. s.,1H, NH).

Step 2:4-{4-[4-(4-tert-Butyl-imidazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester

To the stirred solution of 4-tert-butyl-1H-imidazole (549 mg, 4.4 mmol)in Acetonitrile (10 mL) was added methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(600 mg, 1.3 mmol) and DIPEA (0.66 mL, 3.8 mmol). The resulting solutionwas stirred at room temperature for 2 days. The reaction mixture wasdiluted by EtOAc (60 mL) and the mixture was washed with NaHCO₃ (aq,sat, 20 mL) and brine (20 mL). Organic layer was dried by MgSO4 andconcentrated. The residue was purified by ISCO to give4-{4-[4-(4-tert-Butyl-imidazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester as a white solid (540 mg, 82% yield). ¹H NMR (DMSO-d₆)δ 1.17 (s, 9H, CH₃, CH₃, CH₃), 1.95-2.33 (m, 4H, CH₂, CH₂), 3.49 (s, 3H,CH₃), 4.31-4.58 (m, 2H, CHH, CHH), 4.72 (dd, J=4.5, 10.2 Hz, 1H, CHH),5.11 (s, 2H, CH₂), 5.23 (s, 2H, CH₂), 6.83 (d, J=1.3 Hz, 1H, Ar), 7.18(s, 1H, NHH), 7.24-7.35 (m, 4H, Ar), 7.38-7.53 (m, 3H, Ar), 7.53-7.64(m, 2H, NHH, Ar); LCMS MH=519.

Step 3:3-{4-[4-(4-tert-Butyl-imidazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred solution of methyl5-amino-4-(4-(4-((4-tert-butyl-1H-imidazol-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(540 mg, 1.0 mmol) in Tetrahydrofuran (15 mL) at 0° C. The reactionmixture was stirred at 0° C. for 25 mins before it was diluted by EtOAc(50 mL) and then acidified by HCl (1N, aq, 4 mL) followed by theaddition of NaHCO₃ (aq, sat, 10 mL). The mixture was extracted and theorganic layer was washed with brine (20 mL). The organic layer was driedby MgSO₄ and concentrated to give a white solid. The solid was purifiedby being stirred in acetonitrile (5 mL) and diethyl ether (30 mL) give3-{4-[4-(4-tert-Butyl-imidazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (327, 64% yield). HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, 25/75, (CH₃CN/0.1% H₃PO₄), 3.71 min (97.9%);227-229° C.; ¹H NMR (DMSO-d₆) δ 1.17 (s, 9H, CH₃, CH₃, CH₃), 1.88-2.04(m, 1H, CHH), 2.33-2.47 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.82-3.00(m, 1H, CHH), 4.24 (d, J=17.6 Hz, 1H, CHH), 4.40 (d, J=17.6 Hz, 1H,CHH), 5.11 (s, 3H, CHH, CH₂), 5.22 (s, 2H, CH₂), 6.83 (d, J=1.3 Hz, 1H,imidazole H), 7.31 (t, J=7.4 Hz, 4H, Ar), 7.48 (d, J=8.1 Hz, 3H, Ar),7.60 (d, J=1.1 Hz, 1H, imidazole H), 10.97 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.24, 30.10, 31.11, 31.34, 44.99, 49.04, 51.48, 69.11,112.48, 114.83, 115.17, 127.65, 127.97, 129.72, 129.86, 133.23, 135.97,136.21, 137.62, 151.40, 153.32, 167.90, 170.88, 172.74; LCMS MH=487;Anal. Calcd for C₂₈H₃₀N₄O₄: C, 69.12; H, 6.21; N, 11.51; Found: C,69.02; H, 6.05; N, 11.45. Structure of the compound was confirmed byNOSEY.

5.61(S)-3-[4-(4-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Preparation of(S)-4-[4-(4-Bromomethyl-benzyloxy-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester

To a 2-L round bottom flask was charged methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (30 g, 103mmol), 1,4-bis(bromomethyl)benzene (81 g, 308 mmol) and potassiumcarbonate (14.19 g, 103 mmol) and acetonitrile (1.2 L). The mixture wasstirred at room temperature for 10 min and heated to 50° C. for 12hours. The reaction mixture was allowed to cool to room temperature. Themixture was filtered and the filtrate was concentrated on rota-vap. Theresulted solid was dissolved in CH₂Cl₂ and loaded on 2 silica gelcolumns (330 g each) eluted using CH2Cl2/MeOH to give4-[4-(4-bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as white solid (40 g, 82%). ¹H NMR (DMSO-d₆) δ1.98-2.13 (m, 1H, CHH), 2.14-2.23 (m, 1H, CHH), 2.23-2.32 (m, 2H, CHH,CHH), 3.50 (s, 3H, CH₃), 4.34-4.63 (m, 2H, CH₂), 4.67-4.80 (m, 3H, CH₂,NCH), 5.25 (s, 4H, CH₂), 7.19 (s, 1H, NHH), 7.24-7.34 (m, 2H, Ar),7.41-7.54 (m, 5H, Ar), 7.58 (br. s., 1H, NHH)

Step 2: Preparation of(S)-4-Carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

To the CH₂Cl₂ solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(36.5 g, 77 mmol) was added morpholine (14.72 ml, 169 mmol) at 0° C. Themixture was stirred at 0° C. for 1 hr. The mixture was added 200 mL ofCH₂Cl₂, washed with water (100 mL×2) and brine (100 ml), dried in Na₂SO₄and concentrated to give(S)-4-Carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as white foam (39 g, 100%). M.p. 66-68° C.; WatersSymmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, isocratic 15/85CH₃CN/0.1% H₃PO₄ in H₂O: 7.92 min (99%). ¹H NMR (DMSO-d₆) δ 2.00-2.12(m, 1H, CHH), 2.14-2.22 (m, 1H, CHH), 2.22-2.29 (m, 2H, CHH, CHH),2.30-2.39 (m, 4H, CH₂, CH₂), 3.46 (s, 2H, CH₂), 3.50 (s, 3H, CH₃),3.53-3.63 (m, 4H, CH₂, CH₂), 4.28-4.59 (m, 2H, CH₂), 4.73 (dd, J=4.7,10.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.14-7.23 (m, 1H, NHH), 7.26-7.39(m, 4H, Ar), 7.41-7.51 (m, 3H, Ar), 7.58 (s, 1H, NHH). ¹³C NMR (DMSO-d₆)δ 24.82, 30.33, 44.78, 51.24, 53.12, 53.38, 62.09, 66.14, 69.35, 114.66,115.12, 127.60, 129.00, 129.55, 130.18, 133.43, 135.31, 137.66, 153.42,167.84, 171.73, 172.46; Anal Calcd for C₂₆H₃₁N₃O₆+0.3H₂O: C % 64.13; H %6.54; N % 8.63; Found: C % 63.89; H % 6.39; N % 8.56.

Step 3: Preparation of(S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione

To the THF solution of (S)-methyl5-amino-4-(4-(4-(morpholinomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(45 g, 93 mmol) was added potassium 2-methylpropan-2-olate (10.49 g, 93mmol) portion wise (2 g×5) at −78° C. The mixture was stirred at thistemperature for 30 min then was added 250 mL of 1N HCl solution followedby 200 mL of saturated NaHCO₃ solution. The mixture was extracted withCH₂Cl₂ (150 mL×2). The organic layer was washed with water (50 mL×3) andbrine (100 mL), concentrated on rota-vap to give a white solid, whichwas then recrystallized from CH₃CN (100 mL) to give(S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas white solid (32 g, 76%). mp: 140-142° C. LC-MS m/e=450. HPLC: WatersSymmetry C₁₈, 51 μm, 3.9×150 mm, 1 mL/min, 240 nm, isocratic 15/85CH₃CN/0.1% H₃PO₄ in 5 min: t_(R)=5.61 min (99.5%); Chiral AGP C₁₈4.0×150 mm, 5 μm 10/90 i-propanol/10 mM NH₄Ac in 20 min: t_(R)=10.07 min(99.5%); ¹H NMR (DMSO-d₆) δ 2.28-2.38 (m, 4H, CH₂, CH₂), 2.44 (dd,J=4.2, 13.1 Hz, 1H, CHH), 2.53-2.63 (m, 1H, CHH), 2.79-3.02 (m, 1H,CHH), 3.49-3.69 (m, 4H, CH₂, CH₂), 4.11-4.52 (m, 2H, CH₂), 5.11 (dd,J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.33 (d, J=7.7 Hz, 4H, Ar),7.40-7.52 (m, 3H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.33,31.18, 45.06, 51.55, 53.11, 62.07, 66.14, 69.38, 114.96, 115.20, 127.61,128.97, 129.78, 129.93, 133.28, 135.27, 137.67, 153.48, 167.97, 170.95,172.80. LC-MS: 465; Anal Calcd for C₂₅H₂₇N₃O₅C: 66.80%; H: 6.05%; N:9.35%; Found: C: 66.59%; H: 5.79%; N: 9.26%.

5.623-(1-OXO-4-((4-(((S)-2-(TRIFLUOROMETHYL)PYRROLIDIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: (S)-2-(Trifluoromethyl)pyrrolidine (198 mg, 1.420 mmol) wasadded as solid to a solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(450 mg, 0.947 mmol) in acetonitrile (5 ml). The resulting solution wasstirred for 4 h at room temperature and then for 24 h at 70° C.Additional portions of DIEA (0.165 ml, 0.947 mmol) and(S)-2-(trifluoromethyl)pyrrolidine (60 mg, 0.43 mmol) were charged andthe resulting mixture was stirred at 70° C. for an additional ˜16 h. Themixture was cooled and then concentrated in vacuo. The residue waspartitioned between EtOAc (50 mL) and 1N NaHCO₃ (30 mL) and the aqueouslayer was washed with additional EtOAc (50 mL). The combined organiclayer was washed with brine, dried (Na₂SO₄), and concentrated in vacuoto give methyl5-amino-5-oxo-4-(1-oxo-4-((4-(((S)-2-(trifluoromethyl)pyrrolidin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)pentanoateas a yellow glassy solid (500 mg, 99% crude yield). The crude productwas used in the next step without further purification: LCMS: MH=534.

Step 2: To a solution of methyl5-amino-5-oxo-4-(1-oxo-4-(4-(((S)-2-(trifluoromethyl)pyrrolidin-1-yl)methyl)benzyloxy)isoindolin-2-yl)pentanoate(500 mg, 0.937 mmol) in DMF (5 mL), was added anhydrous potassiumcarbonate (155 mg, 1.125 mmol) and the mixture was stirred at 85° C. for˜17 h. The reaction mixture was cooled to room temperature, diluted withEtOAc (˜150 mL), and washed with 1N aq. NaHCO₃ (30 mL). The organiclayer was washed with water (30 mL) and brine, dried (Na₂SO₄), andconcentrated in vacuo to give a tan oil. The oil was dissolved in DMF (6mL) and purified using reversed-phase preparative HPLC. The product waseluted with an acetonitrile/water gradient (0.1% formic acid in bothmobile phases, 5 to 80% MeCN over 30 minutes) and fractions werecollected by mass trigger. The desired fractions were combined and thenconcentrated in vacuo to give a white solid. Further drying of thissolid in a vacuum oven provided3-(1-oxo-4-((4-(((S)-2-(trifluoromethyl)pyrrolidin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (275 mg, 58% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 45/55 CH₃CN/0.1% H₃PO₄, 5.80 min (99.6%);mp: 178-180° C.; ¹H NMR (DMSO-d₆) δ 1.57-1.91 (m, 3H, CHH, CHH, CHH),1.92-2.15 (m, 2H, CHH, CHH), 2.31-2.48 (m, 2H, CHH, CHH), 2.53-2.65 (m,1H, CHH), 2.75-3.03 (m, 2H, CHH, CHH), 3.44-3.60 (m, 1H, CHH), 3.65 (d,J=13.6 Hz, 1H, CHH), 4.07 (d, J=13.6 Hz, 1H, CHH), 4.25 (d, J=17.6 Hz,1H, CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H,CH), 5.23 (s, 2H, CH₂), 7.33 (d, J=7.7 Hz, 4H, Ar), 7.40-7.54 (m, 3H,Ar), 10.97 (s, 1H, NH);

¹³C NMR (DMSO-d₆) δ 22.33, 24.12, 25.84, 31.18, 45.04, 51.55, 53.56,59.08, 62.79 (q, J=27.5 Hz, CCF₃), 69.38, 114.94, 115.20, 127.66 (q,J=280.6 Hz, CF₃), 127.71, 128.27, 129.78, 129.95, 133.28, 135.24,139.00, 153.48, 167.99, 170.96, 172.81; LCMS: MH=502; Anal Calcd forC₂₆H₂₆F₃N₃O₄: C, 62.27; H, 5.23; N, 8.38; F, 11.36; Found: C, 61.99; H,5.17; N, 8.32; F, 11.37.

5.63(S)-3-METHYL-3-(4-((4-(MORPHOLINOMETHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1:(S)-3-(4-hydroxy-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione

To a mixture of methyl2-(bromomethyl)-3-(tert-butyldimethylsilyloxy)benzoate (4.31 g, 12 mmoland (S)-3-methyl-2,6-dioxopiperidin-3-aminium bromide (2.68 g, 12.00mmol) in acetonitrile (100 mL) was added DIEA (3.4 g, 26.4 mmol). Themixture was heated to 60° C. for 48 h. Then, 50 mL of AcOH was added,and the mixture was heated to 80° C., After 15 min, the mixture wasevaporated to remove the acetonitrile, and the remaining acetic acidsolution was then heated to reflux. After 1 h, the mixture was cooled toroom temperature and filtered, and the filter was rinsed with aceticacid (30 mL) and water (50 mL), and dried under vacuum, providing 2.6 g(79%) as a white solid. ¹H NMR (DMSO-d₆) δ 1.68 (s, 3H), 1.81-1.97 (m,1H), 2.51-2.84 (m, 3H), 4.48 (d, J=17.2 Hz, 1H), 4.59 (d, J=17.4 Hz,1H), 7.00 (d, J=7.9 Hz, 1H), 7.09 (d, J=7.4 Hz, 1H), 7.31 (t J=7.7 Hz,1H), 10.13 (s, 1H), 10.85 (s, 1H).

Step 2:(S)-3-(4-((4-(bromomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione

A mixtureof(S)-3-(4-hydroxy-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione(0.3 g, 1.094 mmol), 1,4-bis(bromomethyl)benzene (0.866 g, 3.28 mmol),and sodium carbonate (0.116 g, 1.094 mmol) in DMF (10 mL) were stirredat room temperature under nitrogen for 16 h. The mixture was partitionedbetween water (75 mL) and ethyl acetate (75 mL), and the organic phasewas evaporated under vacuum. The residue was chromatographed using amethylene chloride-methanol gradient. The product eluted at 2% MeOH.After drying, the yield was 190 mg (38% yield). ¹H NMR (DMSO-d₆) δ 1.69(s, 3H), 1.82-1.94 (m, 1H), 2.52-2.76 (m, 3H), 4.50-4.76 (m, 4H), 5.27(s, 2H), 7.26 (dd, J=7.8, 18.2 Hz, 2H), 7.39-7.59 (m, 5H), 10.84 (s,1H).

Step 3:(S)-3-methyl-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

(S)-3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione(100 mg, 0.219 mmol) was dissolved in acetonitrile (5 mL), andmorpholine (0.021 ml, 0.241 mmol) and DIEA (0.046 ml, 0.262 mmol) wereadded. The mixture was stirred at room temperature for 16 h. Then, themixture was partitioned between EtOAc (50 mL) and water (50 mL) and theorganic phase was washed with water (50 mL), and then extracted with 1NHCl (2×50 mL). The combined acidic aqueous extracts were washed withEtOAc (2×50 mL) and then made basic by the addition of solid sodiumcarbonate, and were then extracted with EtOAc (2×50 mL). The combinedorganic extracts were dried (MgSO₄) and evaporated, providing 90 mg as awhite solid, in 89% yield; mp 178-180° C. HPLC: Waters X-Terra, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, 5/95 to 95/5 CH₃CN-0.1% NH₄(HCO₂) over 5 minthen 10 min 95/5 CH₃CN-0.1% NH₄(HCO₂): 4.63 (96.34%). ¹H NMR (DMSO-d₆) δ1.68 (s, 3H), 1.83-1.93 (m, 1H), 2.28-2.40 (m, 4H), 2.52-2.80 (m, 3H),3.46 (s, 2H), 3.51-3.62 (m, 4H), 4.55 (d, J=17.8 Hz, 1H), 4.68 (d,J=17.8 Hz, 1H), 5.24 (s, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.27-7.38 (m, 3H),7.40-7.50 (m, 3H), 10.85 (s, 1H). ¹³C NMR (DMSO-d₆) δ 20.68, 27.77,29.01, 45.60, 53.15, 57.19, 62.10, 66.17, 69.39, 114.79, 127.71, 129.01,129.74, 129.98, 133.91, 135.28, 137.72, 153.35, 167.00, 172.47, 173.53.Anal. Calcd for C₂₆H₂₉N₃O₅+2.0H₂O: C, 62.51%; H, 6.66%; N, 8.41%; Found:C, 62.52%; H, 6.29%; N, 8.19%.

5.643-(4-((1,5-DIMETHYL-1H-PYRAZOL-3-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: To the solution of methyl 1,5-dimethyl-1H-pyrazole-3-carboxylate(1 g, 6.49 mmol) in THF (20 mL) was added dibal-H (1M in toluene, 19.46mL, 19.46 mmol) at 0° C., the mixture was stirred at room temperatureovernight. A solution of Rochelle's salt (1.0 M, 50 ml) was added;followed by ethyl acetate (50 mL), the resulting suspension was stirredat room temperature until the clear phase separation was achieved, theorganic phase was separated and the aqueous phase was extracted withEtOAc (3×40 ml). The combined organic layers were washed with saturatedaqueous NaHCO₃ (5 mL) and brine, dried over MgSO₄, and concentrated togive (1,5-dimethyl-1H-pyrazol-3-yl)methanol (700 mg, 86% yield); ¹H NMR(DMSO-d₆) δ 2.20 (s, 3H, CH₃), 3.63 (s, 3H, CH₃), 4.29 (d, J=5.9 Hz, 2H,CH₂), 4.84 (t, J=5.8 Hz, 1H, OH), 5.93 (s, 1H, Ar)

Step 2: Polymer-supported thiphenylphosphine (1.6 mmol/g, 3.96 g, 6.34mmol) was added to a stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (927 mg, 3.17mmol) in THF (30 mL) at 0° C., followed by diisopropyl azodicarboxylate(1.28 g, 6.34 mmol), after stirring for 10 minutes,(1,5-dimethyl-1H-pyrazol-3-yl)methanol (400 mg, 3.17 mmol) was added,the mixture was stirred at room temperature overnight and filtered. Theresin was washed with ethyl acetate (10×20 mL). The combined filtratewas evaporated to dryness, the residue was purified by ISCO (40 gcolumn, MeOH/CH₂Cl₂ gradient from 0% to 5% in 40 min) to give methyl5-amino-4-(4-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(340 mg 27% yield); ¹H NMR (DMSO-d₆) δ 1.99-2.29 (m, 7H, CH₂, CH₂, CH₃),3.50 (s, 3H, CH₃), 3.70 (s, 2H, CH₃), 4.26-4.57 (m, 2H, CH₂), 4.70 (s,1H, CH), 5.06 (s, 2H, CH₂), 6.14 (s, 1H, Ar), 7.18 (br. s., 1H, NHH),7.27 (d, J=7.2 Hz, 1H, Ar), 7.32-7.40 (m, 1H, Ar), 7.41-7.50 (m, 1H,Ar), 7.57 (s, 1H, NHH)

Step 3: To a solution of methyl5-amino-4-(4-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(340 mg, 0.849 mmol) in THF (20 mL) was added potassium tert-butoxide(105 mg, 0.934 mmol) at 0° C. The mixture was warmed up to roomtemperature and stirred at room temperature for 1 hour. HCl (1N, 1.5 mL)was added to quenche the reaction, the solvent was evaporated, theresidue was partitioned between ethyl acetate (50 mL) and aqueoussaturated sodium bicarbonate (5 mL). the organic layer was separated,washed with brine, dried over magnesium sulfate, the solvent was removedunder vacuum, the residue was dissoloved in ethyl acetate (3 mL),hexanes (5 mL) was added dropwise, the formed precipitate was collectedby filtration to give3-(4-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(150 mg, 48% yield); mp: 214-216° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.04 (m,1H, CHH), 2.22 (s, 3H, CH₃), 2.34-2.48 (m, 1H, CHH), 2.53-2.67 (m, 1H,CHH), 2.80-3.01 (m, 1H, CHH), 3.70 (s, 3H, CH₃), 4.11-4.43 (m, 2H, CH₂),5.00-5.18 (m, 3H, CH, CH₂), 6.13 (s, 1H, Ar), 7.31 (d, J=7.2 Hz, 1H,Ar), 7.35-7.43 (m, 1H, Ar), 7.43-7.59 (m, 1H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 10.62, 22.31, 31.19, 35.78, 45.07, 51.55, 64.00,104.81, 114.93, 115.07, 129.73, 129.84, 133.21, 139.29, 145.31, 153.46,168.00, 170.96, 172.81; HPLC: Waters Xterra C-18, 3.9×150 mm, 5 μm, 1mL/min, 240 nm, 25/75 CH₃CN/0.1% HCOONH₄ t_(R)=4.51 (98.77%); Anal.Calcd for C19H₂ON₄O₄+0.2H₂O C, 61.35; H, 5.53; N, 15.06; Found: C,61.29; H, 5.30; N, 14.86.

5.65 2-(2,6-DIOXOPIPERIDIN-3-YL)-4-((4-(THIOMORPHOLINOMETHYL)BENZYL)OXY)ISOINDOLINE-1,3-DIONE

Step 1: Dimethyl 3-((4-(hydroxymethyl)benzyl)oxy)phthalate Dimethyl3-hydroxyphthalate (10 g, 47.6 mmol) and(4-(chloromethyl)phenyl)methanol (7.82 g, 50.0 mmol) were dissolved indry DMF (60 mL). To the solution was added K₂CO3 (6.90 g, 50.0 mmol) andthe mixture was stirred at 80° C. for 16 h. The DMF was removed in vacuoand the residue was partitioned between EtOAc (300 mL) and water (100mL). The organic layer was washed with additional water (100 mL) andbrine, dried (Na₂SO₄), and concentrated in vacuo to dimethyl3-((4-(hydroxymethyl)benzyl)oxy)-phthalate as a viscous amber oil (19g): LCMS: MH=331; The crude product was used in the next step withoutfurther purification

Step 2: 3-((4-(Hydroxymethyl)benzyl)oxy)phthalic acid Dimethyl3-(4-(hydroxymethyl)benzyloxy)phthalate (19 g actual wt, 15.72 g, 47.6mmol, assuming quantitative yield from previous step) was dissolved inTHF (30 mL). To the solution was added water (30 mL). Aqueous NaOH (10N, 25 mL, 250 mmol) was added and the mixture was vigorously stirred at70° C. for 2.5 h. The mixture was allowed to cool to rt, concentrated invacuo to a syrup, and then transferred to a flask containing 6 N HCl (45mL) over ice. Immediately, solid precipitated out and the slurry wasdiluted with water (˜60 mL). The mixture was filtered on a mediumfritted funnel with suction. The cake was washed with additional water(˜60 mL), suction dried, and then placed in a vacuum oven at 60° C. for4 h to give 3-((4-(hydroxymethyl)benzyl)oxy)phthalic acid as a paleyellow solid (13.9 g, 97% yield from dimethyl 3-hydroxyphthalate): ¹HNMR (DMSO-d₆) δ 4.41-4.58 (m, 2H, CH₂), 5.17 (s, 3H, CH₂, OH), 7.20-7.64(m, 7H, Ar), 13.02 (br. s., 2H, 2×COOH); ¹³C NMR (DMSO-d₆) δ 62.63,69.73, 117.03, 121.56, 126.46, 126.88, 127.13, 128.91, 129.57, 134.87,142.19, 154.50, 166.45, 167.71; LCMS: MH=303, 94 area % at 240 nm. Thesolid was used in the next step without further purification.

Step 3:2-(2,6-Dioxopiperidin-3-yl)-4-((4-(hydroxymethyl)benzyl)oxy)isoindoline-1,3-dione3-Aminopiperidine-2,6-dione hydrochloride (0.915 g, 5.56 mmol) was addedto a solution of 3-(4-(hydroxymethyl)benzyloxy)phthalic acid (1.4 g,4.63 mmol) in dry pyridine (15 mL) and the mixture was heated to 118° C.in an oil bath for 16 h. The dark reaction mixture was allowed to coolto room temperature and was acidified with slow addition of 1 N HCl (˜25mL). The mixture was further diluted with water (˜170 mL) and thensonicated for ˜30 minutes to help break up solid aggregates. Theresulting dark slurry was filtered on a medium pore fritted funnel andthe dark solid was washed with additional water (70 mL). The cake wassuction dried and then placed in vacuum oven at 60° C. for 2.5 h to give1.6 g of a dark blue solid. The solid was dissolved in a mixture of DCM,MeCN, and MeOH (˜100 mL each) and treated decolorizing charcoal. Themixture was swirled around and then gravity-filtered using filter paper.The filtrate/wash (dark amber color) was treated once again withdecolorizing charcoal and then filtered on a bed of celite. The clearfiltrate was concentrated in vacuo to dryness to give a solid which wastriturated with water and filtered with suction. The cake was washedwith additional water (˜100 mL), suction dried, and then placed invacuum oven at 60° C. for 4 h to give2-(2,6-dioxopiperidin-3-yl)-4-((4-(hydroxymethyl)benzyl)oxy)isoindoline-1,3-dioneas an off-white solid (1.2 μm, 68% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 5.08 min(99.9%); mp: 250-252; ¹H NMR (DMSO-d₆) δ 1.95-2.07 (m, 1H, CHH),2.41-2.67 (m, 2H, CHH, CHH), 2.78-3.00 (m, 1H, CHH), 4.50 (d, J=5.1 Hz,2H, CH₂OH), 5.09 (dd, J=5.4, 12.7 Hz, 1H, CH), 5.19 (t, J=5.6 Hz, 1H,OH), 5.36 (s, 2H, CH₂O), 7.24-7.40 (m, 2H, Ar), 7.41-7.53 (m, 3H, Ar),7.59 (d, J=8.5 Hz, 1H, Ar), 7.82 (dd, J=7.4, 8.5 Hz, 1H, Ar), 11.11 (s,1H, NH); ¹³C NMR (DMSO-d₆) δ 21.88, 30.83, 48.67, 62.53, 69.91, 115.40,116.52, 120.18, 126.44, 127.09, 133.17, 134.31, 136.86, 142.32, 155.42,165.21, 166.68, 169.81, 172.66. LCMS: M+Na=417; MH is not observed inpositive ionization mode; Anal Calcd for C₂₁H₁₈N₂O₆: C, 63.96; H, 4.60;N, 7.10; Found: C, 63.77; H, 4.52; N, 7.32.

Step 4:4-((4-(Bromomethyl)benzyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

A suspension of2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)benzyloxy)isoindoline-1,3-dione(1.05 g, 2.66 mmol) in a mixture of DCM and MeCN (25 mL, 10 mL) wasstirred in an ice bath. To the mixture was added PBr₃ (0.502 mL, 5.32mmol) in one portion. After 5 min, the ice bath was removed and thereaction mixture was stirred at room temperature for −20 h. To thereaction mixture was added NaBr (0.822 g, 7.99 mmol) andtetrabutylammonium bromide (0.077 g, 0.240 mmol) and stirring wascontinued for an additional 14 h at room temperature. The reaction wasconcentrated in vacuo to an off-white solid and the solid was reslurriedin water with vigorous agitation and then filtered (medium frittedfunnel). The cake was washed with copious water (˜250 mL, total volumeof filtrate and washes) and then dried in a vacuum oven at 50° C. togive4-((4-(bromomethyl)benzyl)-oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneas a white solid (1.21 g, 99% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 50/50 CH₃CN/0.1% H₃PO₄, 4.85 min (99.5%);¹H NMR (DMSO-d₆) δ 1.94-2.15 (m, 1H, CHH), 2.42-2.70 (m, 2H, CHH, CHH),2.79-2.99 (m, 1H, CHH), 4.72 (s, 2H, CH₂), 5.10 (dd, J=5.4, 12.9 Hz, 1H,CH), 5.38 (s, 2H, CH₂), 7.38-7.54 (m, 5H, Ar), 7.59 (d, J=8.5 Hz, 1H,Ar), 7.83 (dd, J=7.3, 8.4 Hz, 1H, Ar), 11.11 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 21.95, 30.91, 34.12, 48.75, 69.64, 115.57, 116.62, 120.18,127.48, 129.42, 133.26, 136.33, 136.99, 137.72, 155.37, 165.27, 166.73,169.87, 172.72; LCMS: M+Na=479, 481; MH is not observed.

Step 5:2-(2,6-Dioxopiperidin-3-yl)-4-((4-(thiomorpholinomethyl)benzyl)oxy)isoindoline-1,3-dione

To a slurry of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(250 mg, 0.547 mmol) in MeCN (10 mL), was added thiomorpholine (62.1 mg,0.601 mmol) followed by DIEA (0.143 mL, 0.820 mmol). The resultingsuspension was stirred at room temperature. The reaction mixture becameclear after −15 min of stirring and then, gradually, solids precipitatedout of solution. After −2 h, the reaction mixture was treated with moreDIEA (0.143 mL, 0.820 mmol) and the slurry was heated to 80° C. withconstant stirring for −1 h. The mixture was allowed to cool to roomtemperature slowly with gentle stirring. After 2 h, the slurry wasfiltered on a medium fritted funnel with suction. The residual solid inthe reaction vial was rinsed onto the funnel with minimal MeCN (1 mL).The cake was washed with water (3×10 mL). The remaining solid was driedin vacuum oven at 60 C for 4 h to give2-(2,6-dioxopiperidin-3-yl)-4-((4-(thiomorpholinomethyl)-benzyl)oxy)isoindoline-1,3-dioneas a white solid (225 mg, 86%): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 ml/min, 240 nm, 18/82 CH₃CN/0.1% H₃PO₄, 6.96 min (99.3%); mp:221-223° C.; ¹H NMR (DMSO-d₆) δ 1.96-2.10 (m, 1H, CHH), 2.41-2.66 (m,11H, 4×CH₂, 3×CHH), 2.80-2.97 (m, 1H, CHH), 3.50 (s, 2H, CH₂N), 5.09(dd, J=5.3, 12.8 Hz, 1H, CH), 5.35 (s, 2H, CH₂O), 7.26-7.40 (m, 2H, Ar),7.42-7.53 (m, 2H, Ar), 7.60 (d, J=8.5 Hz, 1H, Ar), 7.83 (dd, J=7.4, 8.5Hz, 1H, Ar), 11.11 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.21, 26.38, 30.16,47.99, 53.65, 61.49, 69.19, 114.75, 115.82, 119.45, 126.52, 128.12,132.51, 134.00, 136.23, 137.16, 154.78, 164.55, 166.00, 169.13, 171.98;LCMS: MH=480; Anal Calcd for C₂₅H₂₅N₃O₅S+0.28H₂O: C, 61.96; H, 5.32; N,8.67; S, 6.62; Found: C, 61.97; H, 5.12; N, 8.63; S, 6.55.

5.663-(4-((6-(MORPHOLINOMETHYL)IMIDAZO[1,2-A]PYRIDINE-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Ethyl 3-bromo-2-oxopropanoate (9.0 g, 46.2 mmol) was added to astirred solution of 5-methylpyridin-2-amine (5.0 g, 46.2 mmol) inethanol (50 mL). The resulting mixture was refluxed for 18 h. Thereaction mixture was cooled and concentrated. Residue was dissolved inCH₂Cl₂ (100 mL) and washed with sat. NaHCO₃ (40 mL), water (40 mL),brine (40 mL) and dried. Solvent was removed and residue was purified bychromatography (SiO₂, 20% EtOAc/CH₂Cl₂ for 20 min then to 100% EtOAcover 30 min) to give ethyl 6-methylimidazo[1,2-a]pyridine-2-carboxylate(3.8 g, 40%): ¹H NMR (CDCl₃) δ 1.44 (t, J=6 Hz, 3H), 2.33 (s, 3H),4.42-4.49 (q, J=6 Hz, 2H), 7.07-7.11 (dd, J=3 and 12 Hz, 1H), 7.56-7.59(d, J=9 Hz, 1H), 7.90-7.91 (d, J=3 Hz, 1H), 8.10 (s, 1H).

Step 2: A mixture of ethyl 6-methylimidazo[1,2-a]pyridine-2-carboxylate(3.7 g, 18.2 mmol) and N-bromosuccinimide (3.2 g, 18.2 mmol) in methylacetate (50 mL) was heated at 60° C. oil bath with a 300 W bulb shiningon the reaction mixture for 3 h. The reaction mixture was cooled anddiluted with EtOAc (50 mL) and washed with water (2×35 mL), brine (35mL) and dried. Solvent was removed and residue was purified bychromatography (SiO₂, 20% EtOAc/CH₂Cl₂ for 25 min) to give ethyl3-bromo-6-methylimidazo[1,2-a]pyridine-2-carboxylate (4.7 g, 90%): ¹HNMR (CDCl₃) δ 1.46 (t, J=6 Hz, 3H), 2.41 (s, 3H), 4.45-4.52 (q, J=6 Hz,2H), 7.16-7.19 (dd, J=3 and 9 Hz, 1H), 7.58-7.61 (d, J=9 Hz, 1H), 7.98(s, 1H); ¹³C NMR (CDCl₃) δ 14.41, 18.45, 61.35, 99.75, 118.46, 121.90,124.57, 129.95, 133.55, 144.27, 162.45.

Step 3: A mixture of ethyl3-bromo-6-methylimidazo[1,2-a]pyridine-2-carboxylate (4.5 g, 15.8 mmol),N-bromosuccinimide (2.8 g, 17.8 mmol) and 2,2′-azobisisobutyronitrile(0.6 g) in CCl₄ (75 mL) was heated at 75° C. oil bath with a 300 W bulbshining on the reaction mixture for 3 h. The reaction mixture was cooledand filtered and washed solid with CH₂Cl₂ (40 mL). Filtrate wasconcentrated and residue was dissolved in CH₂Cl₂ (100 mL) and washedwith water (2×30 mL), brine (30 mL) and dried. Solvent was removed andresidue was purified by chromatography (SiO₂, CH₂Cl₂ for 5 min then to10% EtOAc/CH₂Cl₂ over 5 min and hold for 15 min then to 20% over 5 minand hold for 15 min) to give ethyl3-bromo-6-(bromomethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.5 g,44%); ¹H NMR (CDCl₃) δ 1.47 (t, J=6 Hz, 3H), 4.46-4.52 (q, J=6 Hz, 2H),4.54 (s, 2H), 7.35-7.39 (dd, J=3 and 9 Hz, 1H), 7.68-7.71 (d, J=9 Hz,1H), 8.23 (s, 1H); 3C NMR (CDCl₃) δ 14.35, 29.60, 61.54, 100.79, 119.60,123.28, 125.38, 128.28, 134.56, 144.45, 162.09.

Step 4: A solution of ethyl3-bromo-6-(bromomethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.4 g, 6.7mmol) in acetone (50 mL) and DMF (40 mL) was added to a stirred mixtureof morpholine (0.9 g, 10.1 mol), potassium carbonate (3.3 g, 23.6 mmol)and catalytic amount of 18-crown-6 in acetone (50 mL) at 60° C. oilbath. The reaction mixture was stirred at 60° C. oil bath for 3 h. Thereaction mixture was cooled and filtered. Filtrate was concentrated andresidue was dissolved in EtOAC (100 mL) and washed with water (2×35 mL),brine (35 mL) and dried. Solvent was removed and solid residue wasstirred with ether to give ethyl3-bromo-6-(morpholinomethyl)imidazo[1,2-a]pyridine-2-carboxylate (1.4 g,55%): ¹H NMR (CDCl₃) δ 1.47 (t, J=6 Hz, 3H), 2.48-2.51 (m, 4H), 3.55 (s,2H), 3.72-3.75 (m, 4H), 4.46-4.53 (q, J=6 Hz, 2H), 7.39-7.42 (d, J=9 Hz,1H), 7.63-7.66 (d, J=9 Hz, 1H), 8.12 (s, 1H).

Step 5: LiAlH₄/THF (1M, 3.9 mL, 3.9 mmol) was added slowly to a stirredsolution of ethyl3-bromo-6-(morpholinomethyl)imidazo[1,2-a]pyridine-2-carboxylate (1.2 g,3.3 mmol) in THF (40 mL) at 0-5° C. The reaction mixture was stirred at0° C. for 1 h. The reaction mixture was quenched with water (1 mL), 2NNaOH (1 mL), water (4 mL). The mixture was filtered and washed solidwith CH₂Cl₂ (40 mL). Filtrate was washed with brine (35 mL) and dried.Solvent was removed to give(6-(morpholinomethyl)imidazo[1,2-a]pyridine-2-yl)methanol (0.6 g, 75%):¹H NMR (CDCl₃) δ 2.45-2.50 (m, 4H), 3.46 (s, 2H), 3.70-3.74 (m, 4H),4.84 (s, 2H), 7.19-7.22 (dd, J=3 and 9 Hz, 1H), 7.47-7.52 (m, 2H), 8.02(s, 1H).

Step 6: Triphenylphosphine-polymer bound (2.5 g, 3.4 mmol) in THF (30mL) was cooled in ice bath to 3° C. Diisopropyl azadicarboxylate (0.6 g,3.2 mmol) was added slowly at 3-5° C. After stirred at 3° C. for 10 min,a solution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.7 g, 2.3mmol) and (6-(morpholinomethyl)imidazo[1,2-a]pyridine-2-yl)methanol (0.6g, 2.3 mmol) in THF (70 mL) was added slowly at 5-10° C. After stirredfor 5 min, ice bath was removed and mixture was stirred at roomtemperature overnight. The reaction mixture was filtered and filtratewas concentrated. Residue was dissolved in CH₂Cl₂ (100 mL) and washedwith sat. NaHCO₃ (35 mL), water (35 mL), brine (35 mL) and dried.Solvent was removed and residue was purified by chromatography (SiO₂,CH₂Cl₂ for 5 min then to 3% CH₃OH/CH₂Cl₂ over 5 min and hold for 15 minthen to 5% over 5 min and hold for 15 min then to 10% over 5 min andhold for 10 min) to give methyl5-amino-4-(4-((6-(morpholinomethyl)imidazo[1,2-a]pyridine-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 43%).

Step 7: A solution of methyl5-amino-4-(4-((6-(morpholinomethyl)imidazo[1,2-a]pyridine-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 0.9 mmol) in THF (15 mL) was cooled in dry ice/acetone bath for5 min. A solution of potassium tert-butoxide/THF (1M, 1.0 mL, 1.0 mmol)was added. The reaction mixture was stirred at −78° C. bath for 1 h. Thereaction mixture was quenched with 1N HCl (3 mL) and warmed to roomtemperature. Water (20 mL) was added and basified with sat. NaHCO₃ (8mL) to pH=8. The mixture was extracted with CH₂Cl₂ (3×30 mL) andcombined organic solution was washed with brine (25 mL) and dried.Solvent was removed and residue was precipitated with ether to give3-(4-((6-(morpholinomethyl)imidazo[1,2-a]pyridin-2yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.4 g, 83%): mp 155-157° C.; ¹H NMR (DMSO-d₆) δ 1.97-2.01 (m, 1H),2.36-2.39 (m, 4H), 2.39-2.60 (m, 2H), 2.85-2.96 (m, 1H), 3.44 (s, 2H),3.55-3.58 (m, 4H), 4.20-4.26 (d, J=18 Hz, 1H), 4.36-4.41 (d, J=18 Hz,1H), 5.08-5.14 (dd, J=6 and 12 Hz, 1H), 5.34 (s, 2H), 7.21-7.24 (m, 1H),7.31-7.33 (d, J=9 Hz, 1H), 7.46-7.51 (m, 3H), 8.02 (s, 1H), 8.43 (s,1H), 10.98 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.36, 31.18, 45.06, 51.55,52.97, 59.13, 64.61, 66.13, 111.89, 115.03, 115.18, 116.24, 122.06,125.67, 126.91, 129.77, 133.27, 141.58, 143.90, 153.45, 167.99, 170.96,172.81; Calcd for C₂₆H₂₇N₅O₅+0.2CH₂Cl₂: C, 62.13; H, 5.45; N, 13.83;Found: C, 62.16; H, 5.74; N, 13.13.

5.673-{4-[4-(3,4-DIHYDRO-1H-ISOQUINOLIN-2-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1 Preparation of4-Carbamoyl-4-{4-[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester

To the CH₃CN solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.37 g, 0.778 mmol) was added 1,2,3,4-tetrahydroisoquinoline (0.124 g,0.934 mmol) and DIPEA (0.272 ml, 1.557 mmol). The mixture was stirred atroom temperature for 2 hours. The reaction mixture was concentrated thenextracted with CH₂Cl₂ and water. The organic layer was concentrated andgave4-Carbamoyl-4-{4-[4-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a white solid (0.4 g, 97%). It was used in nextstep directly.

Step 2 Preparation of3-{4-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the CH₃CN solution of methyl5-amino-4-(4-(4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.4 g,0.758 mmol) was added potassium tert-butoxide (0.094 g, 0.834 mmol) at0° C. The mixture was stirred at 0° C. for 1 hour. The reaction wasquenched by adding 5 mL of 1N HCl followed by NaHCO₃ (sat., 5 mL). Themixture was added CH₂Cl₂ (20 mL), water (20 mL) and extracted. Theorganic layer was concentrated and gave a white solid. The solid wasrecrystalized from 4 mL of CH₃CN to give a white solid 170 mg (45%).m.p.: 173-175° C. LC-MS m/e=496. HPLC Waters Symmetry C-18, 3.9×150 mm,5 micro, 1 mL/min, 240 nm, gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂Oduring 5 min and stay at 95/5 for 5 min: 6.43 min (97%). ¹H NMR(DMSO-d₆) δ 1.86-2.11 (m, 1H, CHH), 2.35-2.48 (m, J=4.4, 13.3 Hz, 1H,CHH), 2.52-2.62 (m, 1H, CHH), 2.63-2.74 (m, 2H, CH₂), 2.74-2.84 (m, 2H,CH₂), 2.84-3.02 (m, 1H, CHH), 3.54 (s, 2H, CH₂), 3.65 (s, 2H, CH₂),4.13-4.54 (m, 2H, CH₂), 5.11 (dd, J=5.0, 13.1 Hz, 1H, NCH), 5.24 (s, 2H,CH₂), 6.82-7.20 (m, 4H, Ar), 7.26-7.68 (m, 7H, Ar), 10.97 (s, 1H, NH).¹³C NMR (DMSO-d₆) δ 22.36, 28.64, 31.20, 45.10, 50.16, 51.58, 55.40,61.48, 69.44, 114.98, 115.23, 125.43, 125.94, 126.32, 127.72, 128.41,128.82, 129.82, 129.95, 134.05, 134.69, 135.29, 138.10, 153.51, 170.98,172.83. Anal Calcd for C₃₀H₂₉N₃O₄+0.3H₂O; C % 71.92; H % 5.96; N % 8.39;Found: C % 71.55; H % 5.72; N % 8.22.

5.683-{4-[4-(2,3-DIHYDRO-BENZO[1,4]OXAZIN-4-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the stirred solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.79 mmol) in Acetonitrile (8 mL) was added solution of3,4-dihydro-2H-benzo[b][1,4]oxazine (128 mg, 0.9 mmol) in acetonitrile(2 mL) and DIPEA (0.21 ml, 1.2 mmol) at room temperature. The resultinglight yellow solution was stirred at room temperature for 18 hrs andstirred at 40° C. for 24 hrs. The product was purified by prep HPLC togive3-{4-[4-(2,3-Dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (208 mg, 53% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 55/45, (CH₃CN/0.1% H₃PO₄), 4.50 min(99.0%); mp: 145-147° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.04 (m, 1H, CHH),2.33-2.47 (m, 1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.80-3.01 (m, 1H, CHH),3.35-3.43 (m, 2H, CH₂), 4.14-4.45 (m, 4H, CHH, CHH, CH₂), 4.47 (s, 2H,CH₂), 5.10 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.21 (s, 2H, CH₂), 6.44-6.56(m, 1H, Ar), 6.57-6.76 (m, 3H, Ar), 7.22-7.39 (m, 4H, Ar), 7.39-7.59 (m,3H, Ar), 10.96 (s, 1H, NHH); ¹³C NMR (DMSO-d₆) δ 22.31, 31.16, 45.06,47.06, 51.55, 53.57, 64.03, 69.32, 112.27, 114.91, 115.20, 115.77,116.91, 121.24, 127.20, 127.96, 129.78, 129.95, 133.28, 135.17, 135.21,138.23, 143.46, 153.45, 167.99, 170.95, 172.81; LCMS MH=498; Anal. Calcdfor C₂₉H₂₇N₃O₅+0.3H₂O: C, 69.25; H, 5.53; N, 8.35; Found: C, 69.01; H,5.29; N, 8.25.

5.69 3-{4-[4-(2,3-DIHYDRO-5H-BENZO[F][1,4]OXAZEPIN-4-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the stirred solution of 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (141mg, 0.9 mmol) in Acetonitrile (8 mL) was added3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.79 mmol) and DIPEA (0.21 ml, 1.1 mmol) at room temperature.The reaction mixture was stirred at room temperature for 3.5 hrs before3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30 mg, 0.07 mmol) wasadded. The resulting reaction mixture was stirred at room temperaturefor 17 hrs and the mixture was purified by prep HPLC to give3-{4-[4-(2,3-Dihydro-5H-benzo[f][1,4]oxazepin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (216 mg, 54% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 23/77, (CH₃CN/0.1% H₃PO₄), 4.16 min(99.7%); mp: 148-150° C.; ¹H NMR (DMSO-d₆) δ 1.90-2.04 (m, 1H, CHH),2.34-2.48 (m, 1H, CHH), 2.57 (d, J=17.8 Hz, 1H, CHH), 2.81-3.04 (m, 3H,CH₂, CHH), 3.62 (s, 2H, CH₂), 3.75 (s, 2H, CH₂), 3.95-4.06 (m, 2H, CH₂),4.26 (d, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.03-5.17(m, 1H, CHH), 5.24 (s, 2H, CH₂), 6.91-7.09 (m, 3H, Ar), 7.13-7.25 (m,1H, Ar), 7.33 (d, J=7.2 Hz, 4H, Ar), 7.39-7.54 (m, 3H, Ar), 10.97 (s,1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 45.07, 51.55, 57.28, 57.73,57.87, 69.41, 69.87, 115.00, 115.22, 120.38, 123.08, 127.66, 128.36,128.68, 129.78, 129.95, 130.53, 131.62, 133.30, 135.25, 138.62, 153.48,159.60, 167.99, 170.96, 172.81; LCMS MH=512; Anal. Calcd forC₃₀H₂₉N₃O₅+.4H₂O: C, 69.46; H, 5.79; N, 8.10; Found: C, 69.25; H, 5.53;N, 8.35.

5.70 2-(2,6-DIOXOPIPERIDIN-3-YL)-4-((4-(MORPHOLINOMETHYL)THIAZOL-2-YL)METHOXY)ISOINDOLINE-1,3-DIONE

Step 1: Polymer-supported triphenylphosphine (1.6 mmol/g, 3.5-15.6 mmol)was added to a stirred solution of dimethyl 3-hydroxyphthalate (647 mg,3.08 mmol) in THF (30 mL) at 0° C., followed by diisopropylazodicarboxylate (1.13 g, 5.6 mmol), after stirring for 10 minutes,(4-(morpholinomethyl)thiazol-2-yl)methanol (600 mg, 2.80 mmol) wasadded, the mixture was stirred at room temperature overnight andfiltered. The resin was washed with ethyl acetate (10×30 mL). Thecombined organic layers were evaporated under vacuum. The residue waspurified by ISCO (40 g column, MeOH/CH₂Cl₂ gradient from 0% to 5% in 50min) to give dimethyl3-((4-(morpholinomethyl)thiazol-2-yl)methoxy)phthalate (800 mg, 70%yield).

Step 2: The mixture of dimethyl3-((4-(morpholinomethyl)thiazol-2-yl)methoxy)phthalate (320 mg, 0.787mmol) and sodium hydroxide (10 ml, 30.0 mmol) in ethanol (20 ml) washeated to reflux for 1 hour. The reaction mixture was evaporated todryness under vacuum, water (20 mL) was added, the mixture was extractedwith ethyl acetate (2×10 mL), the aqueous layer was separated andacidified with HCl (3N, 15 mL), then evaporated under vacuum to dryness.The crude was used for next step without further purification.

Step 3: The mixture of3-((4-(morpholinomethyl)thiazol-2-yl)methoxy)phthalic acid (298 mg,0.787 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (155 mg, 0.944mmol) in pyridine (20 mL) was heated to reflux overnight. Pyridine wasevaporated to dryness under vacuum, the residue was partitioned betweensaturated sodium bicarbonate (20 mL) and ethyl acetate (50 mL), theorganic layer was separated, washed with brine, dried over magnesiumsulfate, the solvent was evaporated and the product was purified by prepHPLC (gradient condition: 0-20% acetonitrile in water, 0.1% formic acidin 15 min) to give2-(2,6-dioxopiperidin-3-yl)-4-((4-(morpholinomethyl)thiazol-2-yl)methoxy)isoindoline-1,3-dione(39 mg, 11% yield); mp: 210-212° C.; ¹H NMR (DMSO-d₆) δ 1.92-2.14 (m,1H, CHH), 2.42 (d, J=4.2 Hz, 5H, CHH, CH₂, CH₂), 2.55-2.65 (m, 1H, CHH),2.77-3.02 (m, 1H, CHH), 3.49-3.58 (m, 4H, CH₂, CH₂), 3.60 (s, 2H, CH₂),4.95-5.22 (m, 1H, CH), 5.66 (s, 2H, CH₂), 7.44-7.58 (m, 2H, Ar), 7.65(d, J=8.5 Hz, 1H, Ar), 7.83 (d, J=7.7 Hz, 1H, Ar), 11.11 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 21.93, 30.90, 48.78, 52.99, 57.52, 66.11, 67.56,116.18, 116.82, 118.28, 120.45, 133.26, 136.97, 152.88, 154.60, 164.44,165.07, 166.64, 169.84, 172.72; HPLC: Waters Xterra C-18, 3.9×150 mm, 5μm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% HCOONH₄ t_(R)=4.34 (99.30%);Anal. Calcd for C23H₂₄N₄O₈S C, 53.48; H, 4.68; N, 10.85; Found: C,49.86; H, 4.42; N, 10.50.

5.713-(4-((1-METHYL-5-(MORPHOLINOMETHYL)-1H-PYRAZOL-3-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A 250 mL round bottle flask was charged with methyl1,5-dimethyl-1H-pyrazole-3-carboxylate (2 g, 12.97 mmol), NBS (2.309 g,12.97 mmol), AIBN (0.213 g, 1.297 mmol) as well as CCl4 (40 ml, 415mmol). The mixture was refluxed under nitrogen overnight. The reactionmixture was cooled down, the solid was filtered off, the filtrate wasevaporated to dryness, the residue was purifed by ISCO (120 g column,ethyl acetate/hexanes gradient from 0% to 30% in 50 min, 30% 30 min) togive methyl 5-(bromomethyl)-1-methyl-1H-pyrazole-3-carboxylate (500 mg,17% yield); ¹H NMR (CHLOROFORM-d) δ 3.93 (s, 3H, CH₃), 3.99 (s, 3H,CH₃), 4.47 (s, 2H, CH₂), 6.83 (s, 1H, Ar).

Step 2: To a solution of methyl5-(bromomethyl)-1-methyl-1H-pyrazole-3-carboxylate (500 mg, 2.145 mmol)in acetonitrile (30 mL) were added morpholine (0.280 ml, 3.22 mmol) andtriethyl amine (0.449 ml, 3.22 mmol). The mixture was stirred at roomtemperature for 7 hours. The solvent was evaporated to dryness, theresidue was partitioned between ethyl acetate (50 mL) and aqueoussaturated sodium bicarbonate (20 mL), the organic layer was washed withbrine, dried over magnesium sulfate, the solvent was evaporated to givemethyl 1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-carboxylate (450 mg,88% yield); ¹H NMR (CHLOROFORM-d) δ 2.45 (br. s., 4H, CH₂, CH₂), 3.52(br. s., 2H, CH₂), 3.70 (br. s., 4H, CH₂, CH₂), 3.93 (s, 3H, CH₃), 4.00(s, 3H, CH₃), 6.54-6.87 (m, 1H, Ar).

Step 3: To the mixture of methyl1-methyl-5-(morpholinomethyl)-1H-pyrazole-3-carboxylate (450 mg, 1.881mmol) in THF (15 mL) was added Dibal-H (5.64 mL, 5.64 mmol) at 0° C. Theformed mixture was stirred at room temperature overnight. The solventwas evaporated under vacuum, the residue was partitioned betweenRochelle's salt (1.0M, 10 ml) and ethyl acetate (50 ml), the organicphase was separated and the aqueous phase was extracted with ethylacetate (3×20 ml). The combined organic layers were washed withsaturated aqueous sodium bicarbonate (5 mL) and brine, dried (MgSO₄),and concentrated to give(1-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanol (300 mg, 76%yield); ¹H NMR (CHLOROFORM-d) δ 2.47 (br. s., 4H, CH₂, CH₂), 3.52 (br.s., 2H, CH₂), 3.72 (d, J=2.1 Hz, 4H, CH₂, CH₂), 3.90 (s, 3H, CH₃), 4.65(s, 2H, CH₂), 6.17 (br. s., 1H, Ar).

Step 4: Polymer-supported triphenylphosphine (1.6 mmol/g, 1.78 g, 2.84mmol) was added to a stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (415 mg,1.420 mmol) in THF (30 mL) at 0° C., followed by DIAD (574 mg, 2.84mmol), after stirring for 10 min, the solution of(1-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methanol (300 mg, 1.420mmol) in THF (10 mL) was added, the mixture was stirred at roomtemperature overnight. The resin was filtered and washed with ethylacetate (10×30 mL). The combined filtrate was evaporated to dryness, theresidue was purified by ISCO (40 g column, MeOH in DCM gradient from0-5% in 40 min) to give methyl5-amino-4-(4-((l-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(270 mg, 39% yield); ¹H NMR (DMSO-d₆) δ 1.92-2.30 (m, 4H, CH₂, CH₂),2.30-2.42 (m, 4H, CH₂, CH₂), 3.49 (s, 5H, CH₂, CH₃), 3.52-3.63 (m, 4H,CH₂, CH₂), 3.80 (s, 3H, CH₃), 4.25-4.57 (m, 2H, CH₂), 4.25-4.57 (m, 2H,CH₂), 4.71 (dd, J=4.7, 10.2 Hz, 1H, CH), 5.09 (s, 2H, CH₂), 5.02-5.19(m, 2H, CH₂), 6.27 (s, 1H, Ar), 7.18 (s, 1H, NHH), 7.28 (d, J=7.2 Hz,1H, Ar), 7.32-7.40 (m, 1H, Ar), 7.40-7.51 (m, 1H, Ar), 7.57 (s, 1H,NHH).

Step 5: To a solution of methyl5-amino-4-(4-((1-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(250 mg, 0.515 mmol) in THF was added potassium tert-butoxide (63.6 mg,0.566 mmol) at 0° C., the formed mixture was stirred at room temperaturefor 1 hour. The reaction was quenched by adding aqueous HCl (1N, 1.5mL). The solvent was removed under vacuum, the residue was partitionedbetween saturated sodium bicarbonate (5 mL) and ethyl acetate (30 mL),the organic layer was separated and washed with brine, dried overmagnesium sulfate and filtered, the filtrate was evaporated to dryness,the solid was reslurried with ether (10 mL) and filtered to give3-(4-((1-methyl-5-(morpholinomethyl)-1H-pyrazol-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(130 mg, 56% yield); mp: 125-127° C.; ¹H NMR (DMSO-d₆) δ 1.99 (d, 1H,CHH), 2.35 (d, J=4.0 Hz, 4H, CH₂, CH₂), 2.46 (br. s., 1H, CHH),2.52-2.65 (m, 1H, CHH), 2.82-3.02 (m, 1H, CHH), 3.49 (s, 2H, CH₃),3.51-3.62 (m, 4H, CH₂, CH₂), 3.80 (s, 3H, CH₃), 4.12-4.43 (m, 2H, CH₂),5.03-5.17 (m, 3H, CH₂, CH), 6.26 (s, 1H, Ar), 7.31 (d, J=7.4 Hz, 1H,Ar), 7.35-7.43 (m, 1H, Ar), 7.43-7.55 (m, 1H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.31, 30.38, 31.18, 36.41, 45.07, 51.55, 52.23,52.93, 64.00, 66.08, 106.66, 115.07, 115.18, 129.74, 129.89, 133.24,139.35, 145.27, 153.46, 167.97, 170.96, 172.81; HPLC: Waters XterraC-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% HCOONH₄t_(R)=3.31 (97.56%); Anal. Calcd for C₂₃H₂₇N₅O₅+0.4 EtOAc C, 60.45; H,6.23; N, 14.33; Found: C, 60.10; H, 6.04; N, 14.70.

5.72 4-((4-((7,8-DIHYDRO-1,6-NAPHTHYRIDIN-6(5H)-YL)METHYL)BENZYL)OXY)-2-(2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE

To a mixture of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(250 mg, 0.547 mmol) and 5,6,7,8-tetrahydro-1,6-naphthyridine (81 mg,0.601 mmol) in dry MeCN (10 mL), was added DIEA (0.334 mL, 1.914 mmol).The resulting suspension was stirred at room temperature for 17 h. Thereaction mixture was warmed to 80° C. with vial cap removed. Most of thesolids dissolved and the mixture was concentrated to ˜½ original volume.After ˜2.5 h, the mixture was allowed to cool to room temperature withgentle stirring. A thick slurry formed which was aged at 4° C.overnight. The slurry was treated with DIEA (250 μL) and the mixture wasstirred at room temperature for 30 min. The slurry was then filtered ona medium fritted funnel with suction and the cake was washed with water(˜30 mL). The collected solid was suction dried and then dried furtherin vacuum oven at 50° C. for 6 h to give4-((4-((7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methyl)benzyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneas an off-white solid (275 mg, 99%): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 5.08 min (99.9%);mp: 165-167° C.; ¹H NMR (DMSO-d₆) δ 1.93-2.15 (m, 1H, CHH), 2.38-2.65(m, 2H, CHH, CHH), 2.73-3.01 (m, 5H, CH₂, CH₂, CHH), 3.58 (s, 2H, CH₂),3.70 (s, 2H, CH₂), 5.09 (dd, J=5.4, 12.7 Hz, 1H, CH), 5.37 (s, 2H,CH₂O), 7.12 (dd, J=4.7, 7.7 Hz, 1H, Ar), 7.34-7.54 (m, 6H, Ar), 7.61 (d,J=8.3 Hz, 1H, Ar), 7.83 (dd, J=7.4, 8.5 Hz, 1H, Ar), 8.33 (dd, J=1.7,4.7 Hz, 1H, Ar), 11.11 (s, 1H, NH; 3C NMR (DMSO-d₆) δ 21.95, 30.90,31.89, 48.73, 50.02, 54.26, 61.13, 69.95, 115.50, 116.58, 120.19,120.95, 127.36, 128.84, 129.81, 133.26, 134.17, 134.87, 136.99, 138.05,147.15, 154.38, 155.53, 165.29, 166.75, 169.87, 172.72; LCMS: MH=511;Anal Calcd for C₂₉H₂₆N₄O₅+0.6H₂O: C, 66.81; H, 5.26; N, 10.57; Found: C,66.75; H, 5.28; N, 10.84.

5.733-{1-OXO-4-[4-(4-PHENYL-IMIDAZOL-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the stirred solution of 4-phenyl-1H-imidazole (179 mg, 1.2 mmol) inAcetonitrile (15 mL) was added3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(500 mg, 1.1 mmol) and DIPEA (0.30 ml, 1.7 mmol) at room temperature.The reaction mixture was stirred at room temperature for 19 hrs andheated at 40° C. for 7 hrs before it was added by EtOAc (60 mL), water(15 mL) and brine (15 mL). Then acetonitrile (20 mL) was added todissolve solid. The resulting solution was extracted and organic layerwas concentrated under vacuo. The residue was purified by ISCO to give3-{1-Oxo-4-[4-(4-phenyl-imidazol-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (190 mg, 33% yield). ROESY confirmed the isomericstructure of the product. HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm,1 mL/min, 240 nm, 25/75, (CH₃CN/0.1% H₃PO₄), 4.84 min (99.9%); mp:246-248° C.; ¹H NMR (DMSO-d₆) δ 1.99 (br. s., 1H, CHH), 2.33-2.47 (m,1H, CHH), 2.53-2.60 (m, 1H, CHH), 2.81-2.99 (m, 1H, CHH), 4.23 (d,J=17.6 Hz, 1H, CHH), 4.39 (d, J=17.6 Hz, 1H, CHH), 5.09 (dd, J=5.0, 13.1Hz, 1H, CHH), 5.23 (s, 4H, CH₂, CH₂), 7.12-7.23 (m, 1H, Ar), 7.23-7.39(m, 6H, Ar), 7.39-7.54 (m, 3H, Ar), 7.68 (d, J=1.3 Hz, 1H, imdazole H),7.70-7.78 (m, 2H, Ar), 7.83 (d, J=1.3 Hz, 1H, imdazole H), 10.95 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 22.30, 31.15, 45.04, 49.45, 51.53, 69.17,114.90, 115.23, 115.79, 124.11, 126.17, 127.63, 128.12, 128.40, 129.78,129.93, 133.28, 134.44, 136.17, 137.45, 137.94, 140.90, 153.38, 167.96,170.93, 172.80; LCMS MH=507; Anal. Calcd for C₃₀H₂₆N₄O₄+0.1H₂O: C,70.88; H, 5.19; N, 11.00; Found: C, 70.66; H, 4.87; N, 10.83.

5.743-(4-((3-((4-METHYLPIPERIDIN-1-YL)METHYL)ISOXAZOL-5-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

A mixture of(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)isoxazol-3-yl)methylmethanesulfonate (0.25 g, 0.556 mmol) in acetonitrile (10 mL) was cooledto 0° C. 4-Methylpiperidine (0.066 g, 0.668 mmol) and TEA (0.073 g,0.719 mmol) were added, the ice bath was removed, and the mixturestirred for 16 h. The mixture was partitioned between EtOAc (100 mL) andwater (100 mL), and the organic phase was washed with water (100 mL).Then, the organic phase was extracted with 1% aq. HCl (100 mL), and thisextract was made basic with 5% aq. Na₂CO₃ (50 mL) and extracted intoEtOAc (2×75 mL). The combined organic extracts were washed with water(100 mL), dried (MgSO₄), and evaporated, providing 180 mg (72%), as awhite solid; mp 168-170° C. HPLC: Waters Symmetry C-18, 3.9×150 mm, 5μm, 1 mL/min, 240 nm, 10/90 gradient to 90/10 CH₃CN/0.1% H₃PO₄ in 10min: 4.95 (97.98%). ¹H NMR (DMSO-d₆) δ 0.87 (d, J=6.4 Hz, 3H), 1.01-1.19(m, 2H), 1.21-1.38 (m, 1H), 1.49-1.65 (m, 2H), 1.88-2.04 (m, 3H),2.36-2.47 (m, 1H), 2.54-2.62 (m, 1H), 2.68-2.80 (m, 2H), 2.83-2.99 (m,1H), 3.50 (s, 2H), 4.24 (d, J=17.6 Hz, 1H), 4.41 (d, J=17.6 Hz, 1H),5.11 (dd, J=5.1, 13.2 Hz, 1H), 5.42 (s, 2H), 6.60 (s, 1H), 7.33-7.44 (m,2H), 7.46-7.57 (m, 1H), 10.97 (s, 1H). ¹³C NMR (DMSO-d₆) δ 21.73, 22.33,29.97, 31.20, 33.79, 45.05, 51.61, 52.64, 53.14, 60.72, 104.53, 115.10,115.97, 129.85, 129.98, 133.51, 152.67; 161.56, 167.06, 167.82, 170.94,172.82. Anal. Calcd for C₂₄H₂₈N₄O₅+H₂O: C, 61.26%; H, 6.43%; N, 11.91%;Found: C, 61.41%; H, 6.33%; N, 12.10%.

5.753-(4-((3-(MORPHOLINOMETHYL)IMIDAZO[1,2-A]PYRIDIN-6-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A mixture of ethyl 6-aminonictinate (8.3 g, 49.9 mmol) andchloroacetaldehyde (50% in water, 15.7 g, 99.9 mmol) in CH₃CN (200 mL)was refluxed for 17 h. The reaction mixture was cooled and concentrated.Residue was stirred with CH₂Cl₂ (100 mL) and basified with sat. NaHCO₃(120 mL). Aq. Layer was extracted with CH₂Cl₂ (2×40 mL) and combinedCH₂Cl₂ solution was washed with water (50 mL), brine (50 mL) and dried.Solvent was removed and residue was purified by chromatography (SiO₂,CH₂Cl₂ for 5 min then to 3% CH₃OH/CH₂Cl₂ over 5 min and hold for 15 minthen to 5% over 5 min and hold for 15 min) to give ethylimidazo[1,2-a]pyridine-6-carboxylate (8.3 g, 87%): ¹H NMR (CDCl₃) δ 1.42(t, J=6 Hz, 3H), 4.38-4.45 (q, J=6 Hz, 2H), 7.61-7.75 (m, 4H), 8.93 (s,1H); ¹³C NMR (CDCl₃) δ 14.33, 61.48, 113.49, 116.89, 117.13, 124.09,130.02, 135.33, 145.93, 164.87.

Step 2: A mixture of ethyl imidazo[1,2-a]pyridine-6-carboxylate (2.9 g,15.4 mmon), 37% aq. formaldehyde (1.3 g, 15.4 mmol) and morpholine (1.4g, 15.4 mmol) in glacial acetic acid (5 mL) was warmed at 50° C. for 3 hthen stirred at room temperature overnight. The reaction mixture wasdiluted with CH₂Cl₂ (40 mL) and basified with 2N NaOH to pH=8. Aq. layerwas extracted with CH₂Cl₂ (2×40 mL) and combined CH₂Cl₂ solution waswashed with brine (40 mL) and dried. Solvent was removed to give ethyl3-(morpholinomethyl)imidazo[1,2-a]pyridine-6-carboxylate (4.1 g, 92%):¹H NMR (CDCl₃) δ 1.36 (t, J=6 Hz, 3H), 2.37-2.40 (m, 4H), 3.54-3.57 (m,4H), 3.92 (s, 2H), 4.33-4.40 (q, J=6 Hz, 2H), 7.63-7.65 (m, 3H),9.18-9.19 (d, J=3 Hz, 1H); ¹³C NMR (CDCl₃) δ 14.07, 51.06, 52.81, 60.99,66.18, 115.12, 116.58, 121.62, 122.95, 129.67, 134.98, 145.71, 164.47.

Step 3: A solution ofethyl3-(morpholinomethyl)imidazo[1,2-a]pyridine-6-carboxylate (4.1 g,14.2 mmol) in THF (50 mL) was cooled in ice bath. A solution of lithiumtri-tert-butoxyaluminum hydride/THF (1M, 29 mL, 29 mmol) was addedslowly. After stirred for 5 min, ice bath was removed and mixture wasstirred at room temperature for 2 h. The reaction mixture was cooled andquenched with water (1.5 mL), 2N NaOH (1.5 mL) and water (4.5 mL). Themixture was filtered and washed filter with CH₂Cl₂ (100 mL). Filtratewas washed sat. NaHCO₃ (40 mL), brine (40 mL) and dried. Solvent wasremoved and residue was purified by chromatography (SiO₂, 3%CH₃OH/CH₂Cl₂ for 10 min then to 10% over 10 min and hold for 30 min) togive (3-(morpholinomethyl)imidazo[1,2-a]pyridine-6-yl)methanol (1.5 g,42%): ¹H NMR (CDCl₃) δ 2.42-2.45 (m, 4H), 3.64-3.67 (m, 4H), 3.78 (s,2H), 4.75 (s, 2H), 7.18-7.22 (dd, J=3 and 9 Hz, 1H), 7.48 (s, 1H),7.53-7.56 (d, J=9 Hz, 1H), 8.33 (s, 1H).

Step 4: A mixture of triphenylphosphine-polymer bound (6.2 g, 8.7 mmol)in THF (40 mL) was cooled in ice bath to 3° C.Diisopropylazadicarboxylate (1.5 g, 7.6 mmol) was added slowly at 3-5°C. After stirred at 3° C. for 10 min, a solution of(3-(morpholinomethyl)imidazo[1,2-a]pyridine-6-yl)methanol (1.4 g, 5.8mmol) and methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.7 g, 5.8mmol) in THF (120 mL) was added slowly at 5-8° C. After stirred for 10min, ice bath was removed and mixture was stirred at room temperatureovernight. The reaction mixture was filtered and filtrate wasconcentrated. Residue was dissolved in CH₂Cl₂ (120 mL) and washed withsat. NaHCO₃ (40 mL), water (40 mL), brine (40 mL) and dried. Solvent wasremoved and residue was purified by chromatography (SiO₂, CH₂Cl₂ for 5min then to 3% CH₃OH/CH₂Cl₂ over 5 min and hold for 10 min then to 5%over 5 min and hold for 20 min) to give methyl5-amino-4-(4-((3-(morpholinomethyl)imidazo[1,2-a]pyridine-6-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.3 g, 43%): ¹H NMR (CDCl₃) δ 2.17-2.18 (m, 1H), 2.37-3.45 (m, 7H),3.62-3.65 (m, 7H), 3.82 (s, 2H), 4.38-4.43 (d, J=15 Hz, 1H), 4.51-4.57(d, J=18 Hz, 1H), 4.94-4.96 (m, 1H), 5.18 (s, 2H), 5.68 (b, 1H), 6.51(b, 1H), 7.13-7.16 (dd, J=6 and 9 Hz, 1H), 7.26-7.28 (m, 1H), 7.42-7.47(m, 2H), 7.54 (s, 1H), 7.65-7.68 (d, J=9 Hz, 1H), 8.44 (s, 1H); 3C NMR(CDCl₃) δ 24.24, 30.45, 45.22, 51.80, 52.61, 53.36, 53.89, 66.93, 68.07,114.09, 116.25, 118.08, 120.30, 120.59, 123.97, 124.45, 129.92, 130.23,133.65, 134.44, 146.03, 163.47, 169.14, 171.55, 172.83.

Step 5: A solution of methyl5-amino-4-(4-((3-(morpholinomethyl)imidazo[1,2-a]pyridin-6-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.2 g, 2.4 mmol) in THF (30 mL) was cooled in dry ice/acetone bath for15 min. A solution of potassium tert-butoxide/THF (1M, 2.6 mL, 2.6 mmol)was added slowly. The reaction mixture was stirred in −78° C. bath for 1h then warmed to 0° C. for 1 h. The reaction mixture was quenched with1N HCl (5 mL) and water (20 mL) was added. The mixture was basified withsat. NaHCO₃ to pH=8 and extracted with CH₂Cl₂ (3×30 mL). Combined CH₂Cl₂solution was washed with brine (30 mL) and dried. Solvent was removedand residue was purified by chromatography (SiO₂, CH₂Cl₂ for 5 min thento 3% CH₃OH/CH₂Cl₂ over 5 min and hold for 10 min then to 5% over 5 minand hold for 15 min) to give3-(4-((3-(morpholinomethyl)imidazo[1,2-a]pyridin-6-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.8 g, 69%): mp 170-172° C.; ¹H NMR (DMSO-d₆) δ 1.96-2.01 (m, 1H),2.36-2.60 (m, 6H), 2.85-2.93 (m, 1H), 3.33-3.49 (m, 4H), 4.29 (d, J=18Hz, 1H), 4.40 (d, J=18 Hz, 1H), 5.09-5.15 (dd, J=6 and 12 Hz, 1H), 5.33(s, 2H), 7.35-7.62 (m, 6H), 8.63 (s, 1H), 10.98 (s, 1H); ¹³C NMR(DMSO-d₆) δ 22.39, 31.16, 44.98, 51.04, 52.79, 66.07, 67.25, 115.04,115.44, 116.92, 120.45, 120.58, 124.43, 124.77, 129.83, 133.34, 133.79,144.80, 153.20, 167.94, 170.93, 172.80; Calcd forC₂₆H₂₇N₅O₅+0.2Et₂O+0.0.1CH₂Cl₂: C, 63.00; H, 5.74; N, 13.66; Found: C,62.94; H, 5.98; N, 13.50.

5.763-(4-((4-(MORPHOLINOMETHYL)FURAN-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Redistilled morpholine (3.81 mL, 43.7 mmol) was dissolved in THF(300 mL) and cooled to −78° C. under nitrogen gas condition. To thissolution n-butyllithum (27.3 mL, 43.7 mmol) (1.6 M in hexanes) was addeddropwise and the resulting solution was stirred for further 20 min.subsequently furan-3-carbaldehyde (4 g, 41.6 mmol) in THF (8 mL) wasslowly added, after another 20 min sec-butyllithium (31.2 mL, 43.7 mmol)(1.4 M in cyclohexane) was added dropwise, the resulting mixture wasstirred −78° C. for 2.5 h. Methyl chloroformate (4.33 g, 45.8 mmoL)dissolved in THF (8 mL) was slowly introduced and the reaction mixturewas stirred for 45 min at −78° C. and the additional 20 min at roomtemperature, the solution was poured into ice cold 10% HCl (400 mL, 2.87M). The layers were separated and the aqueous phase was extracted withether (4×100 mL), the combined organic layers were washed with brine,dried over magnesium sulfate, filtered, and concentrated under reducedpressure to dryness, the crude was purified by ISCO (330 g column,EtOAc/hexanes gradient from 0% to 20% in 60 min, 20% for 20 min) to givemethyl 4-formylfuran-2-carboxylate (1.5 g, 23% yield); ¹H NMR(CHLOROFORM-d) δ 3.89 (s, 3H, CH₃), 7.09-7.30 (m, 2H, Ar), 9.75 (s, 1H,CHO).

Step 2: To a solution of methyl 4-formylfuran-2-carboxylate (800 mg,5.19 mmol) in dichloromethane (30 mL) was added morpholine (1.357 mL,15.57 mmol) and acetic acid (1.783 mL, 31.1 mmol). The reaction mixturewas stirred for 10 min, sodium triacetoxyborohydride (3300 mg, 15.57mmol) was added, the mixture was stirred overnight. The reaction mixturewas diluted with dichloromethane (50 mL) and washed with water (2×30mL), saturated sodium bicarbonate (30 mL), brine (30 mL) and dried overmagnesium sulfate, after filtration, the solvent was evaporated undervacuum to give methyl 4-(morpholinomethyl)furan-2-carboxylate; H NMR(CHLOROFORM-d) δ 2.46-2.59 (m, 4H, CH₂, CH₂), 3.62 (s, 2H, CH₂),3.69-3.79 (m, 4H, CH₂, CH₂), 3.89 (s, 3H, CH₃), 6.37 (d, J=3.2 Hz, 1H,Ar), 7.14 (d, J=3.4 Hz, 1H, Ar).

Step 3: To the solution of methyl4-(morpholinomethyl)furan-2-carboxylate (1.12 g, 4.97 mmol) in THF (30mL) was added Dibal-H (14.92 ml, 14.92 mmol) in toluene at 0° C. Theformed mixture was stirred at room temperature overnight. A solution ofRochelle's salt (1.0 M, 50 ml) was added, followed by ethyl acetate (50mL), the resulting suspension was stirred at room temperature, theorganic phase was separated and the aqueous phase was extracted withEtOAc (3×40 ml). The combined organic layers were washed with saturatedaqueous sodium bicarbonate (5 mL) and brine, dried (MgSO₄), andconcentrated to give (4-(morpholinomethyl)furan-2-yl)methanol; ¹H NMR(CHLOROFORM-d) δ 2.43-2.65 (m, 4H, CH₂, CH₂), 3.57 (s, 2H, CH₂),3.68-3.85 (m, 4H, CH₂, CH₂), 4.61 (s, 2H, CH₂), 6.17-6.30 (m, 2H, Ar).

Step 4: Polymer-supported triphenylphosphine (1.6 mmol/g, 1.98 g, 3.16mmol) was added to a stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (615 mg,2.104 mmol) in THF (50 mL) at 0° C., followed by DIAD (638 mg, 3.16mmol), after stirring for 10 minutes,(4-(morpholinomethyl)furan-2-yl)methanol (415 mg, 2.104 mmol) in THF (10mL) was added, the mixture was stirred at room temperature overnight.The mixture was filtered, the resin was washed with ethyl acetate (10×20mL), methanol (5×10 mL), the combined organic phase was evaporated todryness, the crude was purified by ISCO (80 g column, MeOH in DCMgradient from 0-5% in 45 min) to give methyl5-amino-4-(4-((4-(morpholinomethyl)furan-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(440 mg, 44% yield); ¹H NMR (DMSO-d₆) δ 2.24 (d, J=6.6 Hz, 4H, CH₂,CH₂), 2.32-2.40 (m, 4H, CH₂), 3.46-3.52 (m, 5H, CH₂, CH₃), 3.52-3.57 (m,4H, CH₂, CH₂), 4.26-4.55 (m, 2H, CH₂), 4.71 (d, J=5.5 Hz, 1H, CHH), 5.18(s, 2H, CH₂), 6.29 (d, J=3.0 Hz, 1H, Ar), 6.56 (d, J=3.2 Hz, 1H, Ar),7.18 (s, 1H, NHH), 7.30 (d, J=7.4 Hz, 1H, Ar), 7.35-7.42 (m, 1H, Ar),7.46 (d, J=7.7 Hz, 1H, Ar), 7.57 (s, 1H, NHH).

Step 5: To a solution of methyl5-amino-4-(4-((4-(morpholinomethyl)furan-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(440 mg, 0.933 mmol) in THF (20 mL) was added potassium tert-butoxide(126 mg, 1.120 mmol) at 0° C., the mixture was stirred at 0° C. for 1hour, additional pottasium terbutoxide (20 mg, 0.27 mmol) was added, themixture was stirred at room temperature for 1 hour. The reaction wasquenched by adding aqueous HCl (1N, 3 mL). The solvent was removed undervacuum, the residue was partitioned between saturated sodium bicarbonate(10 mL) and ethyl acetate (50 mL), the organic layer was separated andwashed with brine, dried over magnesium sulfate and filtered, thefiltrate was evaporated to dryness to give a solid, the solid wasreslurried in acetonitrile (4 mL) and filtered to give3-(4-((4-(morpholinomethyl)furan-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(160 mg, 39% yield); mp: 168-170° C.; 1H NMR (DMSO-d₆) δ 1.85-2.05 (m,1H, CHH), 2.17-2.50 (m, 5H, CH₂, CH₂, CHH), 2.54-2.65 (m, 1H, CHH), 2.88(d, J=12.3 Hz, 1H, CHH), 3.32 (br. s., 2H, CH₂), 3.56 (br. s., 4H, CH₂,CH₂), 4.13-4.42 (m, 2H, CH₂), 5.10 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.20(s, 2H, CH₂), 6.09-6.52 (m, 1H, Ar), 6.58 (br. s., 1H, Ar), 7.34 (d,J=7.2 Hz, 1H, Ar), 7.38-7.46 (m, 1H, Ar), 7.46-7.56 (m, 1H, Ar), 10.97(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.31, 31.18, 45.06, 51.55, 52.44,54.08, 62.16, 65.81, 109.72, 111.65, 115.42, 115.54, 129.73, 129.99,133.34, 149.29, 152.31, 152.98, 167.90, 170.95, 172.81; HPLC: WatersXterra C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 30/70 CH₃CN/0.1%HCOONH₄ t_(R)=3.13 (96.19%); Anal. Calcd for C₂₃H₂₅N₃O₆+0.5H₂O C, 61.60;H, 5.84; N, 9.37; Found: C, 61.28; H, 5.79; N, 9.31.

5.773-{4-[4-(1-ISOPROPYL-PIPERIDIN-4-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: Preparation of4-{4-[2-(1-Carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperidine-1-carboxylicacid tert-butyl ester

Triphenyl phosphene (polymer-supported, 1.6 mmol/g, 3.3 g) was added toa stirred white suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (2.444 g,8.36 mmol) in THF (100 ml) at 0° C. After ten minutes, diisopropyldiazene-1,2-dicarboxylate (2.470 ml, 12.54 mmol) was added and stirredfor 40 minutes and then tert-butyl4-(4-(hydroxymethyl)benzyl)piperidine-1-carboxylate (3.32 g, 10.87 mmol)in THF (20 ml) was added. The mixture was stirred at 0° C. and warmed upto room temperature overnight. The suspension was filtered, rinsed withMeOH (2×20 ml), CH₂Cl₂(2×30 ml), and the filtrate was evaporated to givean oil, which was dissolved in CH₂Cl₂ (80 ml), washed with Sat NaHCO₃(50 ml), concentrated and then purified by silica gel column to give4-{4-[2-(1-Carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperidine-1-carboxylicacid tert-butyl ester as a foamy oil (2.2 g, 45% yield). It was used inthe next step without further purification.

Step 2: Preparation of4-Carbamoyl-4-[I-oxo-4-(4-piperidin-4-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

To a stirred solution of tert-butyl4-(4-((2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)piperidine-1-carboxylate(2.2 g, 3.80 mmol) in CH₂Cl₂ (10 ml) at room temperature was addedhydrogen chloride (2 M in ether) (10 ml, 38.0 mmol). After four hours,the suspension was filtered, rinsed with ether and the resulting yellowsolid was dried to give 2.02 g, 111% crude yield (HCl salt). The productwas used later in the next step without further purification.

Step 3: Preparation of4-Carbamoyl-4-{4-[4-(1-isopropyl-piperidin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester

To a stirred solution of methyl5-amino-5-oxo-4-(1-oxo-4-(4-(piperidin-4-ylmethyl)benzyloxy)isoindolin-2-yl)pentanoate hydrochloride (1.24 g, 2.403 mmol) in MeOH(15 ml) was added N-ethyl-N-isopropylpropan-2-amine (0.397 ml, 2.403mmol), propan-2-one (1.252 ml, 16.82 mmol), acetic acid (0.069 ml, 1.201mmol), and Sodium cyanoborohyidride (0.302 g, 4.81 mmol). The mixturewas stirred at room temperature overnight. Ice-water (30 ml) was pouredinto the mixture, a precipitate formed, which was extracted with ethylacetate (100 ml), washed with saturated sodium bicarbonate (2×40 ml),brine (30 ml), dried and concentrated to a brown foamy oil (1.11 g, 89%crude yield). It was used in the next step without further purification.

Step 4: Preparation of3-{4-[4-(1-Isopropyl-piperidin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To a stirred solution of methyl5-amino-4-(4-(4-((1-isopropylpiperidin-4-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.09 g, 2.090 mmol) in Tetrahydrofuran (12 ml) in an ice bath (0° C.)was added potassium 2-methylpropan-2-olate (0.246 g, 2.194 mmol). Themixture was stirred at 0° C. for 10 minutes. To the mixture was added 1N HCl (to pH=1) then neutralized with saturated sodium bicarbonate (topH=7) and extracted with ethyl acetate (3×30 ml), washed with brine (20ml), dried over sodium sulfate, and concentrated to a foamy solid, whichwas purified by silica gel column (MeOH/CH₂Cl₂) to give3-{4-[4-(1-Isopropyl-piperidin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas an off-white foamy solid (0.33 g, 32% yield); mp, 182-184° C. HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from10/90 to 70/30 in 5 min, isocratic at 70/30 for 5 min (CH₃CN/0.1%H₃PO₄), 5.19 min (97.4%). 1H NMR (DMSO-d₆) δ 0.92 (d, J=6.4 Hz, 6H, CH₃,CH₃), 1.03-1.22 (m, 2H, CH₂), 1.35-1.60 (m, 3H, CH, CH₂), 1.90-2.10 (m,3H, CHH, CH₂), 2.34-2.48 (m, 2H, CHH, CH), 2.53-2.57 (m, 1H, CHH),2.57-2.78 (m, 4H, CH₂, CH₂), 2.83-3.00 (m, 1H, CHH), 4.19-4.47 (m, 2H,CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.20 (s, 2H, CH₂), 7.17 (d,J=8.1 Hz, 2H, Ar), 7.36 (dd, J=7.9, 18.9 Hz, 4H, Ar), 7.44-7.54 (m, 1H,Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 17.94, 22.36, 31.21, 32.13,37.77, 42.14, 45.09, 48.18, 51.56, 53.78, 69.49, 114.95, 115.19, 127.67,129.05, 129.81, 129.94, 133.29, 133.91, 140.32, 153.54, 168.01, 170.96,172.83. LC/MS m/e=490. Anal Calcd for C₂₉H₃₅N₃O₄ (+0.3H₂O): C, 70.36; H,7.26; N, 8.49; Found: C, 70.18; H, 7.06; N, 8.36.

5.783-{4-[4-(1-METHYL-1H-BENZOIMIDAZOL-2-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: (4-Bromomethyl-phenyl)-acetic acid tert-butyl ester

The stirred solution of 2-(4-(bromomethyl)phenyl)acetic acid (2.6 g,11.35 mmol) in thionyl chloride (20 mL, 274 mmol) was heated to refluxfor 2.5 hrs. The reaction mixture was concentrated under vacuo to giveoff white solid. The white solid was added to the stirred solution of2-methylpropan-2-ol (20 ml, 213 mmol) in DCM (2 mL) under ice/waterbath. And the mixture was stirred under ice/water bath for 2 hrs and atroom temperature for 18 hrs. The reaction mixture was added to CH₂Cl₂(40 mL). The organic phase was washed successively with H₂O (20 mL),NaHCO₃ (sat, aq, 20 mL), and brine (25 mL) and dried over MgSO₄. Organiclayer was concentrated under vacuo to give (4-bromomethyl-phenyl)-acetic acid tert-butyl ester as a light yellow liquid(2.4 g, 74% crude yield). 1H NMR (DMSO-d6): 1.39 (s, 9H, tBu), 3.54 (s,2H, CH2CO2), 4.69 (s, 2H, CH2Br), 7.23, 7.39 (m, 4H, due to impurities).

Step 2:4-[4-(4-tert-Butoxycarbonylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester

To the stirred mixture of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.5 g, 5.13mmol) and tert-butyl 2-(4-(bromomethyl)phenyl)acetate (2.2 g, 7.7 mmol)in Acetonitrile (30 mL) was added POTASSIUM CARBONATE (1.42 g, 10.3mmol). The resulting reaction mixture was stirred at 50° C. for 27 hrsand in between tert-butyl 2-(4-(bromomethyl)phenyl)acetate (800 mg, 2.9mmol) was added in 2 portions. The reaction mixture was filtered and thelight brown solid was washed with acetonitrile (2×20 mL). The filtratewas concentrated under vacuo and the residue was purified by ISCO4-[4-(4-tert-Butoxycarbonylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as a light yellow sticky solid (2.1 g, 82% crudeyield) LCMS MH=497.

Step 3:4-Carbamoyl-4-[4-(4-carboxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

To the stirred solution of methyl5-amino-4-(4-(4-(2-tert-butoxy-2-oxoethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(2.1 g, 4.2 mmol) in DCM (20 mL) at room temperature was added by WATER(0.38 ml, 21.1 mmol) followed by the addition of TFA (1.63 ml, 21.1mmol) slowly. The resulting solution was stirred at room temperature for5 hrs and in between TFA (3.2 mL) and water (0.15 mL) were added. Themixture was kept in fridge overnight and the reaction mixture wasconcentrated under vacuo to give 4-Carbamoyl-4-[4-(4-carboxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methylester as an off white solid (2.3 g, 123% crude yield). ¹H NMR (DMSO-d₆)δ 1.97-2.31 (m, 4H, CH₂, CH₂), 3.50 (s, 3H, CH₃), 3.58 (s, 2H, CH₂),4.41 (d, J=17.8 Hz, 1H, CHH), 4.53 (d, J=17.8 Hz, 1H, CHH), 4.72 (dd,J=4.6, 10.3 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 7.18 (br. s., 1H, NHH),7.24-7.34 (m, 4H, Ar), 7.40-7.50 (m, 3H, Ar), 7.57 (br. s., 1H, NHH);LCMS MH=441.

Step 4:4-Carbamoyl-4-{4-[4-(1-methyl-1H-benzoimidazol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester

The mixture of2-(4-((2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)phenyl)aceticacid (500 mg, 1.1 mmol) and CDI (166 mg, 1.0 mmol) in THF (3 mL). Themixture was stirred at 50° C. for 25 mins before was addedN1-methylbenzene-1,2-diamine (125 mg, 1.022 mmol) in THF (6 mL). Theresulting brown solution was stirred at 50° C. for 21 hrs and thereaction mixture was diluted by EtOAc (40 mL) and washed with NH₄OH (aq,10% wt, 2×20 mL). Organic layer was concentrated under vacuo and theresidue was purified by ISCO to give4-Carbamoyl-4-{4-[4-(1-methyl-1H-benzoimidazol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a pink solid (185 mg, 31% yield); ¹H NMR (DMSO-d₆)δ 1.96-2.34 (m, 4H, CH₂, CH₂), 3.49 (s, 3H, CH₃), 3.71 (s, 3H, CH₃),4.25-4.58 (m, 4H, CHH, CHH, CH₂), 4.65-4.78 (m, 1H, CHH), 5.21 (s, 2H,CH₂), 7.09-7.24 (m, J=1.3, 7.4, 7.4, 7.4, 7.4 Hz, 3H, Ar), 7.25-7.37 (m,4H, Ar, NHH), 7.39-7.51 (m, 4H, Ar, NHH), 7.52-7.62 (m, 2H, Ar); LCMSMH=527.

Step 5:3-{4-[4-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred solution of methyl5-amino-4-(4-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(660 mg, 1.25 mmol) in Tetrahydrofuran (15 mL) at 0° C. (water/ice bath)was added POTASSIUM TERT-BUTOXIDE (155 mg, 1.4 mmol) in one portion. Theresulting mixture was stirred at 0° C. for 1 hr and the reaction mixturewas diluted by DCM (100 mL) followed by the addition of HCl (aq, 1N, 5mL). The mixture was stirred and added by NaHCO₃ (aq., sat., 20 mL). Themixture was extracted and aq layer was extracted by DCM (20 mL). Organiclayers were combined and washed with brine (2×25 mL). Organic layer wasdried by MgSO₄ and concentrated down for ISCO purification to give awhite solid. The white solid was further purified by be stirred inacetonitrile (5 mL) to give3-{4-[4-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (328 mg, 34% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80, (CH₃CN/0.1% H₃PO₄), 7.80 min(99.2%); Mp: 240-242° C.; ¹H NMR (DMSO-d₆) δ 1.88-2.03 (m, 1H, CHH),2.35-2.47 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.80-2.99 (m, 1H, CHH),3.71 (s, 3H, CH₃), 4.15-4.45 (m, 4H, CHH, CHH, CHH, CHH), 5.09 (dd,J=5.1, 13.2 Hz, 1H, CHH), 5.21 (s, 2H, CH₂), 7.10-7.24 (m, J=1.4, 7.4,7.4, 7.4, 7.4 Hz, 2H, Ar), 7.32 (d, J=7.4 Hz, 4H, Ar), 7.40-7.53 (m, 4H,Ar), 7.53-7.60 (m, 1H, Ar), 10.95 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.30, 29.75, 31.16, 32.65, 45.06, 51.53, 69.35, 109.81, 114.91, 115.20,118.41, 121.24, 121.59, 128.06, 128.84, 129.78, 129.93, 133.27, 134.83,135.81, 136.74, 142.19, 153.46, 153.59, 167.99, 170.95, 172.80; LCMSMH=495; Anal. Calcd for C₂₉H₂₆N₄O₄: C, 70.43; H, 6.30; N, 11.33; Found:C, 70.16; H, 5.03; N, 11.31.

5.793-(4-((2-(MORPHOLINOMETHYL)IMIDAZO[1,2-A]PYRIDINE-6-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A mixture of ethyl 6-aminonicotinate (5.0 g, 30.1 mmol) and1,3-dichloropropan-2-one (5.7 g, 45.1 mmol) in acetonitrile (100 mL) wasrefluxed for 17 h. The mixture was concentrated and residue was stirredwith CH₂Cl₂ (100 mL) and sat. NaHCO₃ (35 mL). The organic layer waswashed with brine (40 mL) and dried. Solvent was removed and residue waspurified by chromatography (SiO₂, 30% EtOAc/CH₂Cl₂ for 25 min then to100% EtOAc over 15 min) to give ethyl2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (4.7 g, 65%): ¹HNMR (CDCl₃) δ 1.42 (t, J=6 Hz, 3H), 4.38-4.45 (q, J=6 Hz, 2H), 4.77 (s,2H), 7.56-7.59 (d, J=9 Hz, 1H), 7.70 (s, 1H), 7.74-7.77 (dd, J=3 and 9Hz, 1H), 8.86-8.87 (d, J=3 Hz, 1H).

Step 2: Diisobutylaluminum hydride/Toluene (1M, 22.0 mL, 22.0 mmol) wasadded slowly to a stirred solution of ethyl2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (2.1 g, 8.8 mmol)in THF (60 mL) at 0° C. The reaction mixture was stirred at 0° C. for 4h then quenched with methanol (5 mL). CH₂Cl₂ (70 mL) and sat. NaHCO₃ (40mL) was added and mixture was warmed to room temperature. Aq. layer wasextracted with CH₂Cl₂ (60 mL) and combined CH₂Cl₂ solution was washedwith brine (40 mL) and dried. Solvent was removed and residue wasstirred with ether (25 mL) to give(2-(chloromethyl)imidazo[1,2-a]pyridine-6-yl)methanol (1.1 g, 65%): ¹HNMR (DMSO-d₆) δ 4.60 (s, 2H), 4.75 (s, 2H), 5.22 (b, 1H), 7.19-7.22 (dd,J=3 and 9 Hz, 1H), 7.44-7.47 (d, J=9 Hz, 1H), 7.75 (s, 1H), 8.24 (s,1H).

Step 3: A suspension mixture of(2-(chloromethyl)imidazo[1,2-a]pyridine-6-yl)methanol (1.5 g, 7.4 mmol),morpholine (1.0 g, 11.1 mmol) and N,N-diisopropylethylamine (1.4 g, 11.1mmol) in acetonitrile (30 mL) was heated at 70° C. oil bath for 20 min.The reaction mixture was concentrated and residue was dissolved inCH₂Cl₂ (80 mL) and washed with brine (30 mL) and dried. Solvent wasremoved and residue was purified by chromatography (SiO₂, 3%CH₃OH/CH₂Cl₂ for 10 min then to 10% over 10 min and hold for 40 min) togive (2-(morpholinomethyl)imidazo[1,2-a]pyridin-6-yl)methanol (1.0 g,54%): ¹H NMR (CDCl₃) δ 2.54-2.57 (m, 4H), 3.66-3.74 (m, 6H), 4.40 (b,1H), 4.67 (s, 2H), 7.05-7.09 (dd, J=3 and 9 Hz, 1H), 7.30-7.44 (m, 2H),8.02 (s, 1H).

Step 4: A mixture of triphenylphosphine-polymer bound (4.3 g, 6.1 mmol)in THF (40 mL) was cooled in ice bath to 3° C. Diisopropylazadicarboxylate (1.1 g, 5.3 mmol) was added slowly at 3-5° C. Afterstirred at 3° C. for 10 min, a solution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.2 g, 4.0mmol) and (2-(morpholinomethyl)imidazo[1,2-a]pyridine-6-yl)methanol (1.1g, 4.0 mmol) in THF (80 mL) was added slowly at 5-8° C. After stirred at3° C. for 5 min, ice bath was removed and mixture was stirred at roomtemperature overnight. The reaction mixture was filtered and washedsolid with CH₂Cl₂ (60 mL). Filtrate was concentrated and residue wasdissolved in CH₂Cl₂ (120 mL) and washed with sat. NaHCO₃ (35 mL), water(35 mL), brine (35 mL) and dried. Solvent was removed and residue waspurified by chromatography (SiO₂, CH₂Cl₂ for 5 min then to 3%CH₃OH/CH₂Cl₂ over 5 min and hold for 15 min then to 5% over 5 min andhold for 15 min) to give methyl5-amino-4-(4-((2-(morpholinomethyl)imidazo[1,2-a]pyridin-6-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.2 g, 57%): ¹H NMR (CDCl₃) δ 2.18-2.44 (m, 4H), 2.57-2.60 (m, 4H),3.63 (s, 3H), 3.72-3.76 (m, 6H), 4.38-4.44 (d, J=18 Hz, 1H), 4.49-4.55(d, J=18 Hz, 1H), 4.90-4.95 (dd, J=6 and 9 Hz, 1H), 5.14 (s, 2H), 5.50(b, 1H), 6.38 (b, 1H), 7.12-7.20 (m, 2H), 7.42-7.47 (m, 2H), 7.50-7.63(m, 2H), 8.18 (s, 1H); ¹³C NMR (CDCl₃) δ 24.12, 30.45, 45.21, 51.83,53.82, 53.90, 57.00, 66.98, 67.75, 111.50, 114.32, 116.64, 117.79,120.97, 124.13, 124.26, 129.99, 130.20, 133.65, 144.40, 144.75, 153.35,169.17, 171.46, 172.87.

Step 5: A solution of methyl5-amino-4-(4-((2-(morpholinomethyl)imidazo[1,2-a]pyridin-6-yl)methyoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.2 g, 2.2 mmol) in THF (30 mL) was cooled in ice bath for 15 min. Asolution of potassium tert-butoxide/THF (1M, 2.5 mL, 2.5 mmol) was addedslowly and mixture was stirred in ice bath for 2 h. The reaction mixturewas quenched with 1N HCl (5 mL) and mixture was diluted with CH₂Cl₂ (30mL) and water (20 mL). The mixture was basified with sat. NaHCO₃ (7 mL)to pH=8. Aq. layer was extracted with CH₂Cl₂ (3×30 mL) and combinedCH₂Cl₂ solution was washed with brine (30 mL) and dried. Solvent wasremoved and residue was crystallized from acetone (10 mL) to give3-(4-((2-(morpholinomethyl)imidazo[1,2-a]pyridin-6-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.6 g, 53%): mp 278-280° C.; ¹H NMR (DMSO-d₆) δ 1.97-2.01 (m, 1H),2.40-2.61 (m, 6H), 2.90-2.95 (m, 1H), 3.55-3.59 (m, 6H), 4.29 (d, J=18Hz, 1H), 4.39 (d, J=15 Hz, 1H), 5.08-5.14 (dd, J=6 and 15 Hz, 1H), 5.25(s, 2H), 7.30-7.41 (m, 3H), 7.49-7.51 (m, 2H), 7.83 (s, 1H), 8.66 (s,1H), 10.98 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.36, 31.16, 45.04, 51.56,53.19, 56.27, 66.18, 67.31, 111.68, 115.09, 115.44, 116.34, 120.69,124.87, 125.69, 129.83, 130.02, 133.34, 134.51, 134.58, 153.26, 167.96,170.95, 172.80; Calcd for C₂₆H₂₇N₅O₅: C, 63.79; H, 5.56; N, 14.31;Found: C, 63.38; H, 5.64; N, 14.09.

5.803-{4-[4-(1H-BENZOIMIDAZOL-2-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: (4-Bromomethyl-phenyl)-acetic acid tert-butyl ester

The stirred solution of 2-(4-(bromomethyl)phenyl)acetic acid (2.6 g,11.35 mmol) in thionyl chloride (20 mL, 274 mmol) was heated to refluxfor 2.5 hrs. The reaction mixture was concentrated under vacuo to giveoff white solid. The white solid was added to the stirred solution of2-methylpropan-2-ol (20 ml, 213 mmol) in DCM (2 mL) under ice/waterbath. And the mixture was stirred under ice/water bath for 2 hrs and atroom temperature for 18 hrs. The reaction mixture was added to CH₂Cl₂(40 mL). The organic phase was washed successively with H₂O (20 mL),NaHCO₃ (sat, aq, 20 mL), and brine (25 mL) and dried over MgSO₄. Organiclayer was concentrated under vacuo to give (4-bromomethyl-phenyl)-acetic acid tert-butyl ester as a light yellow liquid(2.4 g, 74% crude yield). 1H NMR (DMSO-d6): 1.39 (s, 9H, tBu), 3.54 (s,2H, CH2CO2), 4.69 (s, 2H, CH2Br), 7.23, 7.39 (m, 4H, due to impurities).

Step 2:4-[4-(4-tert-Butoxycarbonylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester

To the stirred mixture of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.5 g, 5.13mmol) and tert-butyl 2-(4-(bromomethyl)phenyl)acetate (2.2 g, 7.7 mmol)in Acetonitrile (30 mL) was added POTASSIUM CARBONATE (1.42 g, 10.3mmol). The resulting reaction mixture was stirred at 50° C. for 27 hrsand in between tert-butyl 2-(4-(bromomethyl)phenyl)acetate (800 mg, 2.9mmol) was added in 2 portions. The reaction mixture was filtered and thelight brown solid was washed with acetonitrile (2×20 mL). The filtratewas concentrated under vacuo and the residue was purified by ISCO4-[4-(4-tert-Butoxycarbonylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as a light yellow sticky solid (2.1 g, 82% crudeyield) LCMS MH=497.

Step 3:4-Carbamoyl-4-[4-(4-carboxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

To the stirred solution of methyl5-amino-4-(4-(4-(2-tert-butoxy-2-oxoethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(2.1 g, 4.2 mmol) in DCM (20 mL) at room temperature was added by WATER(0.38 ml, 21.1 mmol) followed by the addition of TFA (1.63 ml, 21.1mmol) slowly. The resulting solution was stirred at room temperature for5 hrs and in between TFA (3.2 mL) and water (0.15 mL) were added. Themixture was kept in fridge overnight and the reaction mixture wasconcentrated under vacuo to give 4-Carbamoyl-4-[4-(4-carboxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methylester as an off white solid (2.3 g, 123% crude yield). ¹H NMR (DMSO-d₆)δ 1.97-2.31 (m, 4H, CH₂, CH₂), 3.50 (s, 3H, CH₃), 3.58 (s, 2H, CH₂),4.41 (d, J=17.8 Hz, 1H, CHH), 4.53 (d, J=17.8 Hz, 1H, CHH), 4.72 (dd,J=4.6, 10.3 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 7.18 (br. s., 1H, NHH),7.24-7.34 (m, 4H, Ar), 7.40-7.50 (m, 3H, Ar), 7.57 (br. s., 1H, NHH);LCMS MH=441.

Step 4:4-{4-[4-(1H-Benzoimidazol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester

The solution of2-(4-((2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)phenyl)aceticacid (621 mg, 1.4 mmol) in THF (4 mL) was added CDI (208 mg, 1.28 mmol)in one portion. The mixture was stirred at room temperature for 3 hrsand at 50° C. for 1 hr before was added the solution ofbenzene-1,2-diamine (139 mg, 1.28 mmol) in THF (6 mL). The reactionmixture was stirred at 50° C. for 20 hrs and then stirred at 65° C. for30 hrs. The reaction mixture was diluted by EtOAc (40 mL) and washedwith NH₄OH (aq, 10% wt, 2×20 mL). Organic layer was concentrated undervacuo and the residue was purified by ISCO4-{4-[4-(1H-Benzoimidazol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester as a yellow solid (266 mg, 40% yield). ¹H NMR(DMSO-d₆) δ 1.96-2.32 (m, 4H, CH₂, CH₂), 3.42-3.57 (m, 3H, CH₃), 4.18(s, 2H, CH₂), 4.30-4.58 (m, 2H, CHH, CHH), 4.71 (dd, J=4.7, 10.2 Hz, 1H,CHH), 5.21 (s, 2H, CH₂), 7.05-7.22 (m, 3H, NHH, Ar), 7.22-7.32 (m, 2H,Ar), 7.32-7.49 (m, 6H, Ar), 7.49-7.62 (m, 2H, Ar, NHH), 12.26 (s, 1H,NH); LCMS MH=513.

Step 5:3-{4-[4-(1H-Benzoimidazol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred solution of methyl4-(4-(4-((1H-benzo[d]imidazol-2-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(260 mg, 0.5 mmol) in Tetrahydrofuran (10 mL) at 0° C. was addedPOTASSIUM TERT-BUTOXIDE (62.6 mg, 0.56 mmol). The resulting mixture wasstirred at 0° C. for 2 hrs and in between KOtBu (50 mg, 0.4 mmmol) wasadded in two portions. The resulting reaction mixture was diluted byEtOAc (50 mL) and followed by the addition of HCl (aq, 1N, 3 mL). Theresulting mixture was added by NaHCO₃ (sat., aq, 20 mL) and extracted.Organic layer was concentrated under vacuo and the residue was purifiedby ISCO to give an off white solid (110 mg). The offwhite solid waspurified by being heated in EtOAc (10 mL) at reflux to give3-{4-[4-(1H-Benzoimidazol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (33 mg, 14% yield); HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, 20/80, (CH₃CN/0.1% H₃PO₄), 6.03 min (99.3%);mp: 203-205° C.; ¹H NMR (DMSO-d₆) δ 1.86-2.04 (m, 1H, CHH), 2.33-2.47(m, 1H, CHH), 2.53-2.63 (m, 1H, CHH), 2.81-2.99 (m, 1H, CHH), 4.11-4.44(m, 4H, CHH, CHH, CH₂), 5.09 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.20 (s, 2H,CH₂), 6.99-7.21 (m, 2H, Ar), 7.26-7.60 (m, 9H, Ar), 10.94 (s, 1H, NH),12.27 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.28, 31.16, 34.62, 45.06,51.55, 69.35, 110.84, 114.90, 115.18, 118.22, 120.89, 121.58, 128.02,128.88, 129.77, 129.93, 133.27, 134.82, 137.50, 153.38, 153.45, 167.97,170.93, 172.78; LCMS MH=481; Anal. Calcd for C₂₈H₂₄N₄O₄: C, 69.99; H,5.03; N, 11.66; Found: C, 69.97; H, 4.70; N, 11.58.

5.813-{4-[4-(OCTAHYDRO-ISOINDOL-2-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.357 g, 0.805 mmol) was added Cis-Octa hydro-isoindole hydrochloride(0.195 g, 1.208 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.466 ml,2.82 mmol) at room temperature. The mixture was stirred at roomtemperature overnight. Solvent was evaporated and the resultingoff-white solid was stirred in methylene chloride (100 ml), washed withsaturated sodium bicarbonate (2×80 ml), brine (50 ml), dried andconcentrated to an off-white solid, which was purified by silica gelcolumn (MeOH/CH₂Cl₂) to give3-{4-[4-(Octahydro-isoindol-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (20 mg, 5% yield); mp, not determined. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 70/30 in 5 min, isocratic at 70/30 for 5 min (CH₃CN/0.1% H₃PO₄), 5.17min (97.7%). ¹H NMR (DMSO-d₆) δ 1.18-1.34 (m, 2H, CH₂), 1.35-1.62 (m,6H, CH₂, CH₂, CH₂), 1.92-2.03 (m, 1H, CHH), 2.04-2.22 (m, 2H, CH₂),2.36-2.48 (m, 1H, CHH), 2.53-2.80 (m, 4H, CH₂, CH, CHH), 2.83-3.00 (m,1H, CHH), 3.58-3.86 (m, 2H, CH₂), 4.17-4.49 (m, 2H, CH₂), 5.11 (dd,J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.26-7.54 (m, 7H, Ar),10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.27, 22.36, 31.21, 36.52,45.10, 51.59, 57.64, 69.41, 114.98, 115.23, 127.67, 129.81, 129.95,133.32, 153.50, 168.01, 170.96, 172.82. LC/MS m/e=488. Anal Calcd forC₂₉H₃₃N₃O₄: C, 71.44; H, 6.82; N, 8.62.

5.82 3-(4-((4-((7,8-DIHYDRO-1,6-NAPHTHYRIDIN-6(5H)-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: (S)-Methyl5-amino-4-(4-((4-(bromomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate

1,4-bis(Bromomethyl)benzene (2.71 g, 10.26 mmol) was suspended in dryacetonitrile (40 mL). The slurry was warmed up to 60° C. until fulldissolution occurred (˜15 min). The temperature was reduced to 50° C.and to the solution was added K₂CO₃ (0.473 g, 3.42 mmol) as a solidfollowed by (S)-methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1 g, 3.42mmol, preparation described herein). The resulting white slurry wasstirred at 50° C. for ˜3 h at which time LCMS indicated the phenolstarting material was consumed. The crude reaction mixture was swirledand filtered with suction. The remaining solid in flask and on thefilter funnel was rinsed with minimal MeCM (˜5 mL). The filtrate wasconcentrated in vacuo to give 2.6 g of a white solid. The solid wasdissolved in minimal DCM and purified using a SiO₂ flash column(CombiFlash, 40 g SiO₂ prepacked column). The column was eluted with100% DCM for −15 min, a gradient to 5% MeOH in DCM over 5 min, and thenheld at 5% MeOH in DCM. Fractions were combined and concentrated to give(S)methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas a white solid (1.3 g, 80% yield): ¹H NMR (DMSO-d₆) δ 1.94-2.34 (m,4H, CH₂, CH₂), 3.50 (s, 3H, CH₃), 4.33-4.62 (m, 2H, CH₂), 4.72 (s, 2H,CH₂), 5.25 (s, 2H, CH₂), 5.27-5.36 (m, 1H, CH), 7.19 (br. s., 1H, NH),7.23-7.36 (m, 2H, Ar), 7.40-7.70 (m, 6H, Ar, NH); LCMS: MH=475, 477.

Step 2:(S)-3-(4-(4-(Bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

(S)-Methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(2.05 g, 4.31 mmol) was dissolved in THF (50 mL) and the solution wascooled in dry ice/acetone bath to −76° C. While stirring, solid KO^(t)Bu(0.532 g, 4.74 mmol) was added in one portion to the clear solution. Thereaction mixture became a pale yellow color and was stirred for −90 minat −76° C. A cooled solution of 1 N aq HCl (20 mL) was rapidlytransferred to the reaction mixture, maintaining temperature at −76° C.The mixture immediately turned milky white and the dry C02/acetone bathwas removed, allowing the mixture to warm up to while stirring. Themixture was concentrated on a rotovap to remove most of THF(concentrated to a fixed volume at 160 mbar and water bath ˜35° C.).Upon concentration of reaction mixture, a white solid precipitated out.The white slurry was diluted with more water (˜80 mL) and then suctionfiltered. The cake was washed with copious water (total filtrate volume˜150 mL) and suction dried. The cake was washed with Et₂O (˜50 mL),suction dried and then placed in vacuum oven at 40° C. overnight to give(S)-3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (1.8 g, 94% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 50/50 CH₃CN/0.1% H₃PO₄, 3.70 min (97.9%);mp: 123-125° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.05 (m, 1H, CHH), 2.32-2.48(m, 1H, CHH), 2.52-2.64 (m, 1H, CHH), 2.78-3.04 (m, 1H, CHH), 4.26 (d,J=17.6 Hz, 1H, CHH), 4.43 (d, J=17.6 Hz, 1H, CHH), 4.72 (s, 2H, CH₂),5.11 (dd, J=5.0, 13.1 Hz, 1H, CH), 5.25 (s, 2H, CH₂), 7.24-7.36 (m, 2H,Ar), 7.41-7.54 (m, 5H, Ar), 10.83-11.07 (m, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.33, 31.18, 34.15, 45.06, 51.56, 69.12, 114.94, 115.28, 127.95,128.33, 129.41, 129.80, 131.93, 133.31, 136.78, 153.36, 167.97, 170.95,172.81; LCMS: MH=443, 445. The solid was used in the next step withoutfurther purification. The stereochemistry of the benzyl bromide productis deduced from the stereochemical outcome of products derived from it.

Step 3:3-(4-((4-((7,8-Dihydro-1,6-naphthyridin-6(5H)-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

In a 20-mL scintillation vial, MeCN (5 mL, 96 mmol) was added to amixture of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.451 mmol) and 5,6,7,8-tetrahydro-1,6-naphthyridine (72.6 mg,0.541 mmol). DIEA (0.236 mL, 1.354 mmol) was added to the mixture. Themixture was stirred at room temperature for 1 h. The suspension wasfiltered. The solid was washed with Et₂O and dried in vacuum oven togive3-(4-((4-((7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (198 mg, 88% yield): mp: 163-165° C.; HPLC: WatersSymmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 15/85 CH₃CN/0.1%H₃PO₄, 3.66 min (99.2%); ¹H NMR (DMSO-d₆) δ 1.90-2.05 (m, 1H, CHH),2.34-2.48 (m, 1H, CHH), 2.52-2.64 (m, 1H, CHH), 2.70-2.82 (m, 2H, CH₂),2.82-3.04 (m, 3H, CHH, CH₂), 3.57 (s, 2H, CH₂), 3.69 (s, 2H, CH₂), 4.26(d, J=17.4 Hz, 1H, CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1,13.2 Hz, 1H, CH), 5.24 (s, 2H, CH₂O), 7.12 (dd, J=4.8, 7.6 Hz, 1H, Ar),7.27-7.36 (m, 2H, Ar), 7.37-7.58 (m, 6H, Ar), 8.33 (dd, J=1.5, 4.7 Hz,1H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 31.18, 31.92,45.07, 50.00, 51.56, 54.27, 61.14, 69.41, 114.97, 115.22, 120.95,127.73, 128.79, 129.80, 129.83, 129.93, 133.30, 134.16, 135.35, 138.10,147.15, 153.49, 154.40, 167.99, 170.96, 172.80; LCMS: MH=497; Anal Calcdfor C₂₉H₂₈N₄O₄+1.14H₂O: C, 67.36; H, 5.90; N, 10.83; Found: C, 67.36; H,5.93; N, 10.68.

5.833-(1-OXO-4-((4-((2-(TRIFLUOROMETHYL)-5,6-DIHYDRO-[1,2,4]TRIAZOLO[1,5-A]PYRAZIN-7(8H)-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1:3-[4-(4-Hydroxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione

To a round bottom flask charged with methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (5 g, 17.11mmol), (4-(chloromethyl)phenyl)methanol (2.81 g, 17.96 mmol), andanhydrous potassium carbonate (2.60 g, 18.82 mmol), was added DMF (50mL). The reaction mixture was stirred at room temperature and reactionprogress was followed by LCMS. After ˜3 h, DIEA (3.29 mL, 18.82 mmol)was added and the reaction was stirred overnight. After ˜18 h, solid KI(1.6 g, 9.64 mmol) was added and the mixture was warmed to 40° C. andstirred for −2 days. The reaction mixture, containing a mixture ofdesired product and uncyclized glutarimide precursor, was warmed furtherto 80° C. for ˜30 h. The crude reaction mixture was cooled to rt,filtered on a fritted funnel, and the removed solids were washed withminimal MeCN. The combined filtrate and washes were concentrated on arotovap until DMF started to distill. The concentrated mixture wasdiluted with aqueous 1 N HCl (˜150 mL) and water (˜700 mL) and extractedwith EtOAc (2×700 mL). The combined organic layer was washed with 1 NHCl (200 mL), 1 N Na₂CO₃ (2×300 mL), and brine. The solution was dried(Na₂SO₄) and concentrated in vacuo to −400 mL. Activated charcoal (˜11g) was added and the slurry was agitated for −15 min then filtered on abed of Celite on a medium fritted funnel with suction. The clearfiltrate was concentrated in vacuo to give an off-white solid (4.1 g).The solid was slurried in MeCN (60 mL) with aid of sonication and gentleheating. The mixture was heated for −30 min at 60° C. with agitation andthen allowed to cool to room temperature. Et₂O (˜30 mL) was added andthe slurry was agitated with intermittent sonication. The solid wascollected by filtration on a medium fritted funnel and the cake waswashed with additional Et₂O and then suction dried. The remaining solidwas dried in a vacuum oven at 40° C. to give3-[4-(4-hydroxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (3.4 g, 52% yield): ¹H NMR (DMSO-d₆) δ 1.90-2.04 (m,1H, CHH), 2.34-2.49 (m, 1H, CHH), 2.57 (d, J=18.1 Hz, 1H, CHH),2.81-3.01 (m, 1H, CHH), 4.25 (d, J=17.6 Hz, 1H, CHH), 4.41 (d, J=17.4Hz, 1H, CHH), 4.50 (d, J=5.9 Hz, 2H, CH₂), 5.11 (dd, J=5.1, 13.0 Hz, 1H,CH), 5.18 (t, J=5.8 Hz, 1H, OH), 5.23 (s, 2H, CH₂), 7.28-7.39 (m, 4H,Ar), 7.41-7.56 (m, 3H, Ar), 10.96 (s, 1H, NH); LCMS: MH=381.

Step 2:3-[4-(4-Bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione

To a well stirred suspension of3-(4-(4-(hydroxymethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(2.4 g, 6.31 mmol) in dry MeCN (40 mL) at 0° C., was added PBr₃ (1.19mL, 12.6 mmol) via a syringe. To the stirred mixture was addedtetrabutyl ammonium bromide (0.203 g, 0.631 mmol). After ˜5 min, the icebath was removed and the reaction mixture was allowed to stir at roomtemperature for ˜4.5 h. The reaction mixture was poured into a flaskwith water (200 mL) on ice. The resulting thick slurry was filtered on amedium fritted funnel with suction. Residual solid in the flask wastransferred onto the filter funnel with additional water. The cake waswashed with copious water and hexanes (˜150 mL) and then suction dried.The solid was slurried with Et₂O (˜50 mL) and agitated for 10 min thencollected by suction filtration. The cake was washed with additionalEt₂O (˜50 mL) and then dried in a vacuum oven at 40° C. overnight togive3-[4-(4-bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas white solid (2.61 g, 93%): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 ml/min, 240 nm, 50/50 CH₃CN/0.1% H₃PO₄, 3.78 min (96.6%); ¹H NMR(MeCN-d₃) δ 2.08-2.22 (m, J=2.5, 5.2, 5.2, 12.8 Hz, 1H, CHH), 2.45 (qd,J=4.9, 13.1 Hz, 1H, CHH), 2.62-2.94 (m, 2H, CHH, CHH), 4.31 (d, J=17.0Hz, 1H, CHH), 4.41 (d, J=17.2 Hz, 1H, CHH), 4.62 (s, 2H, CH₂), 5.09 (dd,J=5.1, 13.4 Hz, 1H, CH), 5.24 (s, 2H, CH₂), 7.24 (d, J=8.1 Hz, 1H, Ar),7.38 (d, J=7.0 Hz, 1H, Ar), 7.42-7.55 (m, 5H, Ar), 8.83 (br. s., 1H,NH); ¹³C NMR (MeCN-d₃) δ 22.37, 30.89, 33.02, 44.83, 51.64, 69.26,114.62, 115.21, 127.79, 129.01, 129.55, 130.12, 133.27, 136.87, 137.98,153.52, 168.29, 170.13, 171.79; LCMS: MH=443, 445.

Step 3:3-(1-Oxo-4-((4-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione

To a slurry of(3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.451 mmol)) and2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine(95 mg, 0.496 mmol) in dry MeCN (5 mL, 96 mmol), was added DIEA (0.197mL, 1.128 mmol) and the resulting white suspension was stirred at roomtemperature for 2 h and heat to 40° C. for 4 additional hours Themixture was cooled at 0° C. The suspension was filtered. The solid waswashed with water (˜50 mL) and dried in vacuum oven at 50° C. to give3-(1-oxo-4-((4-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (135 mg, 54% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH₃CN/0.1% H₃PO₄, 6.33 min (98.2%);mp: 139-142° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.05 (m, 1H, CHH), 2.34-2.48(m, 1H, CHH), 2.57 (d, J=19.1 Hz, 1H, CHH), 2.82-2.98 (m, 1H, CHH), 3.02(t, J=5.5 Hz, 2H, CH₂), 3.80 (s, 2H, CH₂), 3.82 (s, 2H, CH₂), 4.20-4.31(m, 3H, CHH, CH₂), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2Hz, 1H, CH), 5.25 (s, 2H, CH₂), 7.30-7.36 (m, 2H, Ar), 7.38-7.44 (m, 2H,Ar), 7.45-7.54 (m, 3H, Ar), 10.96 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.34, 31.16, 45.07, 46.54, 47.73, 49.17, 51.56, 59.42, 69.35, 114.99,115.23, 127.80, 128.92, 129.80, 129.95, 133.30, 135.73, 137.05, 152.82,153.46, 167.97, 170.95, 172.80; Two carbon signals are not observed(probably due to splitting of CF₃, and CCF₃); LCMS: MH=555; Anal Calcdfor C₂₇H₂₅F₃N₆O₄+0.5H₂O: C, 57.55; H, 4.65; N, 14.91; F, 10.11; Found:C, 57.42; H, 4.32; N, 14.60; F, 9.92.

5.843-{4-[4-(6-METHOXY-3,4-DIHYDRO-1H-ISOINOLIN-2-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.365 g, 0.823 mmol) was added 6-methoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride (0.247 g, 1.235 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.408 ml, 2.470 mmol) at roomtemperature overnight. Solvent was evaporated and the residue wasstirred in CH₂Cl₂ (100 ml) and washed with sat NaHCO₃ (2×30 ml), brine(20 ml) and evaporated to an oil, which was purified by silica gelcolumn (MeOH/CH₂Cl₂) to give3-{4-[4-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione(0.26 g, 60% yield); mp, 169-171° C. HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 70/30 in 5 min,isocratic at 70/30 for 5 min (CH₃CN/0.1% H₃PO₄), 4.72 min (98.3%). ¹HNMR (DMSO-d₆) δ 1.90-2.06 (m, 1H, CHH), 2.32-2.46 (m, 1H, CHH),2.53-2.71 (m, 3H, CH₂, CHH), 2.71-2.83 (m, 2H, CH₂), 2.83-3.02 (m, 1H,CHH), 3.46 (br. s., 2H, CH₂), 3.55-3.81 (m, 5H, CH₂, CH₃), 4.18-4.50 (m,2H, CH₂), 5.12 (dd, J=5.2, 13.3 Hz, 1H, NCH), 5.23 (br. s., 2H, CH₂),6.58-6.74 (m, 2H, Ar), 6.89 (d, J=9.1 Hz, 1H, Ar), 7.24-7.62 (m, 7H,Ar), 10.98 (br. s., 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.36, 28.94, 31.21,45.10, 50.12, 51.58, 54.92, 61.51, 69.45, 111.91, 112.93, 114.97,115.24, 126.73, 127.26, 127.72, 128.82, 129.81, 129.94, 131.81, 133.31,135.22, 138.28, 153.51, 157.45, 168.01, 169.07, 170.96, 172.83. LC/MSm/e=526. Anal Calcd for C₃₁H₃₁N₃O₅ (+1.1H₂O): C, 68.27; H, 6.14; N,7.70; Found: C, 68.08; H, 5.92; N, 7.47.

5.853-(4-((3-((4-ISOPROPYLPIPERIDIN-1-YL)METHYL)ISOXAZOL-5-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

A mixture of(5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)isoxazol-3-yl)methylmethanesulfonate (0.28 g, 0.623 mmol) in acetonitrile (10 mL) wasstirred at room temperature. 4-Isopropylpiperidine (0.095 g, 0.748 mmol)and DIEA (0.11 g, 0.810 mmol) were added, and the mixture stirred atroom temperature for 3 h. Then, the mixture was evaporated under vacuum.The residue was partitioned between EtOAc (75 mL) and water (75 mL), andthe organic phase was washed with water (75 mL). Then the organic phasewas extracted with 1N HCl (2×50 mL). The combined aqueous extracts werewashed with EtOAc (75 mL) and then made basic with solid sodiumcarbonate, and the resulting mixture was extracted with EtOAc (2×50 mL).The combined organic extracts were washed with water (75 mL), dried(MgSO₄) and evaporated, providing 180 mg (60%) as a white solid; mp173-175° C. HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240nm, 10/90 gradient to 90/10 CH₃CN/0.1% H₃PO₄ in 10 min: 5.65 (96.83%).¹H NMR (DMSO-d₆) δ 0.83 (d, J=6.6 Hz, 6H), 0.97 (br. s., 1H), 1.09-1.24(m, 2H), 1.30-1.46 (m, 1H), 1.58 (d, J=11.9 Hz, 2H), 1.80-2.06 (m, 3H),2.36-2.47 (m, 1H), 2.52-2.64 (m, 1H), 2.72-3.01 (m, 3H), 3.41-3.63 (m,2H), 4.25 (d, J=17.6 Hz, 1H), 4.41 (d, J=17.6 Hz, 1H), 5.11 (dd, J=5.0,13.1 Hz, 1H), 5.43 (s, 2H), 6.62 (s, 1H), 7.39 (t, J=7.0 Hz, 2H),7.46-7.57 (m, 1H), 10.97 (s, 1H). ¹³C NMR (DMSO-d₆) δ 19.62, 22.35,28.69, 31.21, 31.85, 41.46, 45.05, 51.61, 52.58, 53.49, 60.72, 104.57,115.11, 115.99, 129.85, 129.98, 133.51, 152.67, 161.50, 167.12, 167.82,170.92, 172.80. Anal. Calcd for C₂₆H₃₂N₄O₅+0.2H₂O: C, 64.50%; H, 6.75%;N, 11.57%; Found: C, 64.48%; H, 6.73%; N, 11.31%.

5.863-{4-[4-(2-METHYL-4-PHENYL-IMIDAZOL-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the stirred solution of 2-methyl-4-phenyl-1H-imidazole (157 mg, 0.99mmol) in Acetonitrile (15 mL) was added3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(400 mg, 0.9 mmol) and DIPEA (0.24 ml, 1.35 mmol) at room temperature.The reaction mixture was stirred at room temperature for 4 days beforethe reaction mixture was diluted by EtOAc (40 mL) and NaHCO₃ (aq, sat.,20 mL). The mixture was extracted. Some solid was formed and the mixturewas filtered. And the solid was dissolved in DCM (20 mL) and MeOH (5mL). All organic layers were combined and dried by MgSO₄ andconcentrated. The residue was purified by ISCO to give3-{4-[4-(2-Methyl-4-phenyl-imidazol-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (310 mg, 66% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75, (CH₃CN/0.1% H₃PO₄), 5.26 min(99.6%); mp: 270-272° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.03 (m, 1H, CHH),2.30 (s, 3H, CH₃), 2.43 (dd, J=4.3, 13.0 Hz, 1H, CHH), 2.53-2.63 (m, 1H,CHH), 2.82-2.97 (m, 1H, CHH), 4.23 (d, J=17.6 Hz, 1H, CHH), 4.39 (d,J=17.6 Hz, 1H, CHH), 5.04-5.16 (m, 1H, CHH), 5.18 (s, 2H, CH₂), 5.23 (s,2H, CH₂), 7.10-7.20 (m, 1H, Ar), 7.20-7.26 (m, J=8.1 Hz, 2H, Ar),7.26-7.36 (m, 4H, Ar), 7.42-7.54 (m, 3H, Ar), 7.62 (s, 1H, NH),7.64-7.75 (m, 2H, Ar), 10.96 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 12.76,22.31, 31.16, 45.04, 48.59, 51.55, 69.17, 114.93, 115.25, 116.49,123.92, 125.88, 127.15, 128.14, 128.36, 129.78, 129.95, 133.30, 134.58,135.98, 137.15, 138.50, 144.57, 153.39, 167.97, 170.93, 172.80; LCMSMH=521; Anal. Calcd for C₃₁H₂₈N₄O₄+0.3H₂O: C, 70.79; H, 5.48; N, 10.65;Found: C, 70.68; H, 5.21; N, 10.52. The regio isomeric structure wasconfirmed by ROESY.

5.872-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYL}-1,2,3,4-TETRAHYDRO-ISOQUINOLINE-7-CARBONITRILE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.358 g, 0.808 mmol) was added1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (0.192 g, 1.211 mmol), asuspension formed. Then N-ethyl-N-isopropylpropan-2-amine (0.267 ml,1.615 mmol) was added, which became a clear solution. It became turbidagain in 10 minutes. The mixture was stirred at room temperatureovernight. Solvent was evaporated, to the resulting solid was addedether (30 ml), stirred, filtered and the filter was purified by silicagel column (MeOH/CH₂Cl₂) to give2-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-1,2,3,4-tetrahydro-isoquinoline-7-carbonitrile(0.324 g, 77% yield); mp, 145-147° C. HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 90/10 in 5min, isocratic at 90/10 for 5 min (CH₃CN/0.1% H₃PO₄), 4.62 min (95.8%).¹H NMR (DMSO-d₆) δ 1.92-2.06 (m, 1H, CHH), 2.35-2.48 (m, 1H, CHH),2.53-2.64 (m, 1H, CHH), 2.64-2.75 (m, 2H, CH₂), 2.82-3.00 (m, 3H, CHH,CH₂), 3.58 (s, 2H, CH₂), 3.67 (s, 2H, CH₂), 4.20-4.48 (m, 2H, CH₂), 5.12(dd, J=5.1, 13.2 Hz, 1H, NCH), 5.24 (s, 2H, CH₂), 7.26-7.42 (m, 5H, Ar),7.43-7.61 (m, 5H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 28.88,31.20, 45.09, 49.39, 61.14, 69.42, 108.23, 114.98, 115.24, 119.01,127.77, 128.80, 129.49, 129.69, 129.82, 129.94, 130.32, 133.31, 135.38,136.40, 137.99, 140.51, 153.51, 168.01, 170.98, 172.83. LC/MS m/e=521.Anal Calcd for C₃₁H₂₈N₄O₄ (+0.8H₂O): C, 69.60; H, 5.58; N, 10.47; Found:C, 69.21; H, 5.21; N, 10.22.

5.883-(4-((5-(MORPHOLINOMETHYL)PYRIDIN-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A solution of methyl 5-(chloromethyl)picolinate (3.00 g, 16.14mmol) in acetonitrile (30 mL) was added to morpholine (4.5 mL, 51.7mmol). The resulting dark solution was stirred at room temperature for 3h. The reaction mixture was diluted with Et₂O (˜100 mL) and the solidthat formed was removed by filtration. The filtrate was concentrated andthe oily residue was partitioned between EtOAc (125 mL) and 1N NaHCO₃(50 mL). The aqueous layer was washed with more EtOAc (˜100 mL). Thecombined organic layers was washed with brine, dried (Na₂SO₄), andconcentrated in vacuo to give methyl 5-(morpholinomethyl)picolinate as adark oil (3.4 g, 89% yield). ¹H NMR (DMSO-d₆) δ 2.29-2.42 (m, 4H, CH₂,CH₂), 3.54-3.61 (m, 6H, CH₂, CH₂, CH₂), 3.88 (s, 3H, CH₃), 7.91 (dd,J=2.2, 8.0 Hz, 1H, Pyr), 8.03 (d, J=8.5 Hz, 1H, Pyr), 8.64 (d, J=1.5 Hz,1H, Pyr); ¹³C NMR (DMSO-d₆) δ 52.28, 53.02, 59.03, 66.08, 124.51,137.47, 137.57, 146.28, 150.08, 165.11. The product was used in the nextstep without further purification.

Step 2: To a well stirred solution of methyl5-(morpholinomethyl)picolinate (3.4 g, 14.39 mmol) in THF (30 ml) at 2°C. (in ice bath), a 1M solution of lithium aluminum hydride (15.83 ml,15.83 mmol) in THF was added via a syringe. Gas evolved and the reactionmixture changed was stirred at ˜2° C. for ˜1 h. The reaction wasquenched by slow addition of 1N NaHCO₃ (20 mL) at 0° C. and then dilutedwith EtOAc (˜300 mL) and H₂O (100 mL). The mixture was agitated and then1 N aq. solution of Rochelle's salt was added to break up emulsion. Theaqueous layer was extracted with EtOAc (300 mL). The aqueous layer wassaturated with solid NaCl and extracted once more with EtOAc. Thecombined organic layer was washed with minimal brine, dried (Na₂SO₄),and concentrated in vacuo to give the crude(5-(morpholinomethyl)pyridin-2-yl)methanol as an orange oil (1.7 g, 56%crude yield). The crude product was used in the next step withoutpurification. ¹H NMR (DMSO-d₆) δ 2.30-2.38 (m, 4H, CH₂, CH₂), 3.47 (s,2H, CH₂), 3.51-3.63 (m, 4H, CH₂, CH₂), 4.54 (d, J=5.5 Hz, 2H, CH₂OH),5.36 (t, J=5.8 Hz, 1H, OH), 7.42 (d, J=7.9 Hz, 1H, Pyr), 7.70 (dd,J=2.2, 8.0 Hz, 1H, Pyr), 8.38 (d, J=1.7 Hz, 1H, Pyr).

Step 3: Methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0 g, 3.42mmol) and triphenyl phosphine on polystyrene (1.6 mmol/g resin) (4.28 g,6.84 mmol) were slurried in THF (30 mL) at room temperature. The resinwas allowed to swell with gentle stirring for about 5 minutes then themixture was cooled in ice bath at 0° C. and DIAD (1.330 mL, 6.84 mmol)was added using a syringe in a rapid dropwise fashion. After about 10minutes, (5-(morpholinomethyl)pyridin-2-yl)methanol (1.069 g, 5.13 mmol)in THF (5 mL) was added. The resulting mixture was stirred at roomtemperature. After about 1.5 h, the resin was filtered on a coursefritted funnel and the resin was rinsed 3× with successive swell/shrinkcycles (DCM/MeOH washes). The filtrate (amber color) was concentrated invacuo to give the crude methyl5-amino-4-(4-((5-(morpholinomethyl)pyridin-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas a brown oil (3.3 g). The crude product was used in the next stepwithout further purification.

Step 4: To a stirred solution of crude methyl5-amino-4-(4-((5-(morpholinomethyl)pyridin-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1 g, 1.036 mmol) in dry THF (10 mL) at 0° C. (ice bath) was addedpotassium tert-butoxide (0.233 g, 2.072 mmol). The resulting mixture wasstirred at 0° C. for ˜10 min, then allowed to warm up to rt. After ˜3 h,the reaction mixture was transferred to a chilled solution of 20% AcOHin MeCN (˜50 mL) on ice. The resulting solution was concentrated todryness and the brown oily residue was partitioned between EtOAc (150mL) and 1N NaHCO₃ (35 mL). The aqueous layer was extracted withadditional EtOAc (˜150 mL). The combined organic layer was washed withbrine, dried (Na₂SO₄), and concentrated to dryness to give a glassysolid. The solid was recrystallized from MeCN/Et₂O, filtered, and washedwith additional Et₂O to give3-(4-((5-(morpholinomethyl)pyridin-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a light tan solid (78 mg, 17% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO4, 6.45 min(97.3%); mp: 194-196° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.05 (m, 1H, CHH),2.30-2.41 (m, 4H, CH₂, CH₂), 2.40-2.48 (m, 1H, CHH), 2.55-2.67 (m, 1H,CHH), 2.82-3.01 (m, 1H, CHH), 3.51 (br. s., 2H, CH₂N), 3.53-3.70 (m, 4H,CH₂, CH₂), 4.30 (d, J=17.6 Hz, 1H, CHH), 4.46 (d, J=17.6 Hz, 1H, CHH),5.12 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.31 (s, 2H, CH₂O), 7.25-7.39 (m, 2H,Ar), 7.43-7.52 (m, 1H, Ar), 7.55 (d, J=7.9 Hz, 1H, Ar), 7.76 (d, J=7.6Hz, 1H, Ar), 8.50 (s, 1H, Ar), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.36, 31.16, 45.06, 51.56, 52.96, 59.16, 66.08, 70.37, 114.96, 115.41,121.31, 129.84, 129.92, 132.53, 133.34, 137.50, 149.56, 153.27, 155.02,167.94, 170.96, 172.83; LCMS: MH=451; Anal Calcd for: C₂₄H₂₆N₄O₅: C,63.99; H, 5.82; N, 12.44; Found: C, 58.77; H, 5.34; N, 11.46; Cl, 1.10.

5.89 4-CARBAMOYL-4-(4-HYDROXY-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-BUTYRICACID METHYL ESTER FORMIC ACID

Step 1: Preparation of4-Carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

Polymer-supported triphenylphosphene (1.6 mmol/g, 3.0 g, 3.78 mmol) wasadded to a stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.50 g, 1.72 mmol) in THF (30 mL) at 0° C. After 5minutes, diisopropyl diazene-1,2-dicarboxylate (0.75 ml, 3.78 mmol) wasadded. After 30 minutes, (4-Morpholin-4-ylmethyl-phenyl)-methanol (0.71g, 3.43 mmol) was added. The mixture was stirred overnight at roomtemperature then filtered, washed w/MeOH (10 mL), methylene chloride (10mL), and repeated three more times w/MeOH (10 mL), methylene chloride(10 mL). The combined filtrate was evaporated in vacuo to give an oil,which was purified by ISCO flash column chromatography (120 g,MeOH/CH₂Cl₂ gradient from 0% to 5% in 60 min) to give4-Carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a foamy white solid (0.62 g, 75% yield). It wasused in the next step without further purification.

Step 2: Preparation of3-[4-(4-Morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione

Potassium tert-butoxide (0.14 g, 1.25 mmol) was added to a stirredsolution of4-Carbamoyl-4-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.60 g, 1.25 mmol) in THF (15 mL) at 0° C. for 10minutes. The mixture was quenched with a couple pipetful of 1N HCl andneutralized with saturated sodium bicarbonate to pH=8. The mixture wasethyl acetate (3×20 mL). The combined ethyl acetate phases wereevaporated and then purified by ISCO flash column chromatography (40 g,MeOH/CH₂Cl₂ gradient from 0% to 5% in 40 min) to give3-[4-(4-Morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas an off-white solid (0.13 g, 23% yield); mp, 208-210° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 15/85 in10 min (CH₃CN/0.1% H₃PO₄): t_(R)=3.86 min (98.1%). LC/MS (Acquity UPLCBEH C18, 2.1×50 mm, 0.8 mL/min, 1.7 μm, 5/95 gradient to 85/15 in 5 min,isocratic at 85/15 for 1 min (CH₃CN/0.1% HCOOH: water/0.1% HCOOH)):m/e=450. ¹H NMR (DMSO-d₆) δ 1.90-2.05 (m, 1H, CH), 2.28-2.40 (m, 4H,2CH₂), 2.40-2.46 (m, 1H, CH), 2.54-2.65 (m, 1H, CH), 2.82-3.00 (m, 1H,CH), 3.46 (s, 2H, CH₂), 3.51-3.65 (m, 4H, 2CH₂), 4.20-4.48 (m, 2H,ArCH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H, ArCH₂O), 7.33(d, J=7.6 Hz, 4H, Arh), 7.39-7.55 (m, 3H, ArH), 10.97 (s, 1H, NH). ¹³CNMR (DMSO-d₆) δ 22.36, 31.20, 45.09, 51.58, 53.14, 62.10, 66.17, 69.41,114.98, 115.24, 127.65, 128.99, 129.82, 129.95, 133.32, 135.30, 137.70,153.50, 167.99, 170.98, 172.83. Anal Calcd for C₂₅H₂₇N₃O₅. C, 66.80; H,6.05; N, 9.35; Found: C, 66.49; H, 5.90; N, 9.29.

Step 3: Preparation of4-Carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester formic acid

Hydrogen peroxide (10.24 g, 90.2 mmol) was added to a stirred solutionof3-(4-(4-(morpholinomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.507 g, 1.128 mmol) in acetonitrile (30 ml) and Water (10 ml) at roomtemperature. The solution was stirred at room temperature overnight.Solvent was evaporated and the residue was purified by preparative HPLC(MeCN/water, with 0.1% HCOOH) to give4-Carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester formic acid (0.23 g, 44% yield); mp, 154-156° C. HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from10/90 to 90/10 in 5 min, isocratic at 90/10 for 5 min (CH₃CN/0.1%H₃PO₄), 4.35 min (98.7%). ¹H NMR (DMSO-d₆) δ 1.91-2.05 (m, 1H, CHH),2.35-2.48 (m, 1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.83-2.99 (m, 1H, CHH),3.04 (d, J=12.3 Hz, 2H, CH₂), 3.54 (td, J=3.8, 11.8 Hz, 2H, CH₂),3.71-3.82 (m, 2H, CH₂), 3.92-4.07 (m, 2H, CH₂), 4.22-4.49 (m, 2H, CH₂),4.63 (s, 2H, CH₂), 5.11 (dd, J=5.2, 13.3 Hz, 1H, NCH), 5.28 (s, 2H,CH₂), 7.29-7.38 (m, 2H, Ar), 7.44-7.66 (m, 5H, Ar), 11.02 (s, 1H, NH).¹³C NMR (DMSO-d₆) δ 22.38, 31.20, 45.08, 51.59, 60.67, 62.05, 69.15,71.81, 114.95, 115.33, 127.21, 128.77, 129.84, 129.97, 133.12, 133.35,137.87, 153.40, 164.93, 167.98, 170.98, 172.83. LC/MS m/e=466. AnalCalcd for C₂₅H₂₇N₃O₆ ((+1.0 HCOOH, +1.3H₂O): C, 58.38; H, 5.95; N, 7.85;Found: C, 58.21; H, 6.30; N, 7.81.

5.903-(4-((5-(MORPHOLINOMETHYL)ISOXAZOL-3-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (2 g, 11.69 mmol)was dissoloved in DCM (30 ml) and triphenylphosphine (3.37 g, 12.85mmol) and CBr₄ (3.68 g, 11.10 mmol) were added at 0° C., The mixture wasstirred for 2 hours at 0° C. The mixture was concentrated under vacuum,the residue was purified by ISCO (80 g column, ethyl acetate in hexanesgradient from o-20% in 40 min) to give ethyl5-(bromomethyl)isoxazole-3-carboxylate (2.5 g, 91% yield); ¹H NMR(CHLOROFORM-d) δ 1.43 (t, J=7.1 Hz, 3H, CH₃), 4.46 (q, J=7.2 Hz, 2H,CH₂), 4.50 (s, 2H, CH₂), 6.74 (s, 1H, Ar).

Step 2: The mixture of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (2.3g, 9.83 mmol), morpholine (1.284 ml, 14.74 mmol) and triethyl amine(2.055 ml, 14.74 mmol) in acetonitrile was stirred at room temperatureovernight. The solvent was evaporated to dryness under vacuum, theresidue was partitoned between ethyl acetate (100 mL) and saturatedsodium bicarbonate (30 mL), the organic layer was separated and washedwith brine, dried over MgSO₄, the solvent was removed under reducedpressure to give ethyl 5-(morpholinomethyl)isoxazole-3-carboxylate (2.3g, 95% yield); ¹H NMR (CHLOROF-ORM-d) δ 1.43 (t, J=7.2 Hz, 3H, CH₃),2.45-2.64 (m, 4H, CH₂, CH₂), 3.67-3.81 (m, 6H, CH₂, CH₂, CH₂), 4.45 (q,J=7.2 Hz, 2H, CH₂), 6.65 (s, 1H, Ar).

Step 3: To the solution of ethyl5-(morpholinomethyl)isoxazole-3-carboxylate (2.3 g, 9.57 mmol) in THF(50 mL) was added Dibal-H (28.7 ml, 28.7 mmol) at 0° C. The formedmixture was warmed up to room temperature and stirrred at roomtemperature. The mixture was quenched with 1 M Rochelle's salt andextracted with EtOAc (3×50) mL, the combined organic layer was washedwith saturated sodium bicarbonate, brine and dried over magnesiumsulfate. The organic solvent was evaporated to give(5-(morpholinomethyl)isoxazol-3-yl)methanol (1.48 g, 78% yield); ¹H NMR(CHLOROFORM-d) δ 2.50-2.66 (m, 4H, CH₂), 3.70 (s, 2H, CH₂), 3.72-3.82(m, 4H, CH₂, CH₂), 4.76 (br. s., 2H, CH₂), 6.29 (s, 1H, Ar).

Step 3: A mixture of (5-(morpholinomethyl)isoxazol-3-yl)methanol (740mg, 3.73 mmol), methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1091 mg,3.73 mmol) and polymer supported triphenylphosphine (1.86 g, 5.6 mmol, 3mmol/g) in THF (100 mL) was cooled to 0° C., and DIAD (1132 mg, 5.6mmol) was added, The formed mixture was stirred at room temperatureovernight. The reaction mixture was filtered through celite, the resinwas washed with ethyl acetate (5×200 mL), the combined organic layer wasevaporated to dryness, the residue was purified by ISCO (80 g column,MeOH in DCM gradient from 0-5% in 50 min) to give methyl5-amino-4-(4-((5-(morpholinomethyl)isoxazol-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(600 mg, 34% yield); ¹H NMR (DMSO-d₆) δ 1.98-2.32 (m, 4H, CH₂, CH₂),2.36-2.45 (m, 4H, CH₂, CH₂), 3.50 (s, 3H, CH₃), 3.53-3.62 (m, 4H, CH₂,CH₂), 3.69 (s, 2H, CH₂), 4.29-4.60 (m, 2H, CH₂), 4.66-4.82 (m, 1H, CH),5.33 (s, 2H, CH₂), 6.59 (s, 1H, Ar), 7.19 (s, 1H, NHH), 7.33 (dd, J=4.2,7.6 Hz, 2H, Ar), 7.47 (d, J=7.6 Hz, 1H, Ar), 7.59 (s, 1H, NHH.

Step 4: To a mixture of methyl5-amino-4-(4-((5-(morpholinomethyl)isoxazol-3-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(580 mg, 1.228 mmol) in THF (30 ml) was added potassium tert-butoxide(152 mg, 1.350 mmol) at 0° C. The formed mixture was stirred at 0° C.for 0.5 hour and warmed up to room temperature in 0.5 hour. The reactionwas quenched with HCl (1N, 3 mL), THF was evaporated under vacuum,saturated sodium bicarbonate (20 mL) was added, the formed precipitatewas collected by filtration and reslurried in acetonitrile (7 mL) togive3-(4-((5-(morpholinomethyl)isoxa-zol-3-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (325 mg, 60 yield); mp 218-220° C. HPLC: (Waters XterraC-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% HCOONH₄):3.45 (98.98%). 1H NMR (DMSO-d₆) δ 1.86-2.08 (m, 1H), 2.31-2.48 (m, 5H),2.52-2.68 (m, 1H), 2.81-3.01 (m, 1H), 3.48-3.64 (m, 4H), 3.69 (s, 2H),4.26 (d, J=17.6 Hz, 1H), 4.34-4.53 (m, J=17.6 Hz, 1H), 5.11 (dd, J=5.1,13.2 Hz, 1H), 5.34 (s, 2H), 6.57 (s, 1H), 7.25-7.43 (m, 2H), 7.44-7.59(m, 1H), 10.98 (s, 1H). ¹³C NMR (DMSO-d₆) δ 22.38, 31.20, 45.03, 51.61,52.51, 52.73, 61.62, 66.03, 103.25, 115.13, 115.83, 129.87, 130.01,133.42, 152.95, 160.09, 167.86, 169.84, 170.94, 172.82. Anal. Calcd forC₂₂H₂₄N₄O₆: C, 59.99%; H, 5.49%; N, 12.72%; Found: C, 59.00%; H, 5.03%;N, 12.14%.

5.913-(4-((3-METHYLISOXAZOL-5-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A mixture of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1 g, 3.42mmol) and (3-methylisoxazol-5-yl)methanol (0.387 g, 3.42 mmol) in THF(50 mL) was cooled to 0° C. Triphenylphosphine, polymer-bound, 3 mmol/g(2.3 g, 6.84 mmol) was added, followed by DIAD (1.347 ml, 6.84 mmol).The ice bath was allowed to melt and the mixture stirred at ambienttemperature for 16 h. The mixture was evaporated to dryness and theresidue was loaded dry-loaded directly onto a silica gel column, runninga hexanes-EtOAc gradient. The product eluted at 100% EtOAc, and theyield of the curde mixture thus obtained was 0.75 g (57%).

Step 2: The residue from step 1 was dissolved in THF (50 mL) and cooledto 0° C. Then, potassium tert-butoxide (0.230 g, 2.053 mmol) was added.After 30 min, the reaction was quenched by the addition of AcOH (0.5 mL)and the mixture was evaporated under vacuum. Then the mixture wassuspended in a mixture of EtOAc (100 mL) and 10% aqueous sodiumcarbonate solution (100 mL), and this biphasic mixture was stirred for 1h, and then filtered, and the filter was washed with water (50 mL) andethyl acetate (50 mL). After drying under vacuum, the product wasobtained as a white solid, 510 mg, in 42% yield; mp 278 −280° C. HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 30/70CH₃CN/0.1% H₃PO₄: 3.27 (96.63%). ¹H NMR (DMSO-d₆) δ 1.91-2.07 (m, 1H),2.24 (s, 3H), 2.34-2.48 (m, 1H), 2.52-2.68 (m, 1H), 2.80-3.01 (m, 1H),4.24 (d, J=17.6 Hz, 1H), 4.33-4.47 (m, J=17.6 Hz, 1H), 5.10 (dd, J=4.9,13.0 Hz, 1H), 5.40 (s, 2H), 6.54 (s, 1H), 7.28-7.45 (m, 2H), 7.46-7.60(m, 1H), 10.99 (s, 1H). ¹³C NMR (DMSO-d₆) δ 10.89, 22.39, 31.24, 45.00,51.64, 60.65, 105.05, 115.03, 115.93, 129.85, 129.95, 133.51, 152.68,159.68, 166.88, 167.83, 171.05, 172.96. Anal. Calcd for C₁₈H₁₇N₃O₅+0.3CH₂Cl₂: C, 57.72%; H, 4.66%; N, 11.03%; Found: C, 57.61%; H, 4.47%; N,10.70%.

5.923-(1-OXO-4-((4-((3-(TRIFLUOROMETHYL)-5,6-DIHYDRO-[1,2,4]TRIAZOLO[4,3-a]PYRAZIN-7(8H)-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a mixture of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.451 mmol) and3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinehydrochloride (113 mg, 0.496 mmol) in dry MeCN (5 mL, 96 mmol), wasadded DIEA (0.276 mL, 1.579 mmol) at room temperature and then resultingmix was stirred at room temperature overnight. To the mixture was addedtetrabutylammonium bromide (10.18 mg, 0.032 mmol) and raised temp to 40°C. over weekend. The reaction mixture was transferred portionwise withstirring to a flask with water (˜50 mL). The resulting suspension wasstirred at room temperature with intermittant sonication to break upsolid aggregates. After ˜1 h of stirring the solid was filtered andwashed with small portion of water. The crude mixture was purified byPrep HPLC to give3-(1-oxo-4-((4-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dioneas an off-white solid (120 mg, 48% yield): HPLC: Waters Symmetry C₁₈, 5Lm, 3.9×150 mm, 1 ml/min, 240 nm, 35/65 CH₃CN/0.1% H₃PO₄, 4.86 min(97.7%); mp: 142-144° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.04 (m, OH, CHH),2.45 (dd, J=4.3, 13.0 Hz, 0H, CHH), 2.57 (dd, J=2.3, 15.5 Hz, OH, CHH),2.81-2.99 (m, 3H, CH₂, CHH), 3.78 (s, 2H, CH₂), 3.84 (s, 2H, CH₂), 4.15(t, J=5.4 Hz, 2H, CH₂), 4.26 (d, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.6Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.25 (s, 2H, CH₂), 7.33(d, J=7.6 Hz, 2H, Ar), 7.38-7.44 (m, 2H, Ar), 7.45-7.58 (m, 3H, Ar),10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.34, 31.16, 43.03, 45.06,47.30, 48.09, 51.56, 59.51, 69.35, 114.99, 115.23, 116.80 (q, J=269.6Hz, M₁₀), 127.79, 128.94, 129.78, 129.93, 133.30, 135.75, 136.99, 142.31(q, J=38.5 Hz, M₂₄), 152.28, 153.46, 167.97, 170.95, 172.80; LCMS:MH=555; Anal Calcd for C₂₇H₂₅F₃N₆O₄+0.75H₂O: C, 57.09; H, 4.70; N,14.79; F, 10.03; Found: C, 57.09; H, 4.55; N, 14.74; F, 9.76.

5.931′-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYL}-[2,4′]BIPYRIDINYL-1′-IUMFORMATE

To the CH₂Cl₂ (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.52 g, 1.173 mmol) was added 2,4′-bipyridine (0.220 g, 1.408 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.388 ml, 2.346 mmol). It was a lightgreen clear solution and was stirred at room temperature overnight. Theoily solid/oil was stirred in water (20 ml) and CH₂Cl₂ (25 ml) for onehour. The aq phase was separated and further washed with CH₂Cl₂ (2×30ml). The combined CH₂Cl₂ phases were extracted with water (2×10 ml). Thecombined water phases were evaporated in a 50° C. water bath to give anoff white solid, which was purified by preparative HPLC (MeCN/water in0.1% HCOOH) to give1′-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-[2,4′]bipyridinyl-1′-iumformate (0.213 g, 35% yield); mp, 132-134° C. HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 90/10in 5 min, isocratic at 90/10 in 5 min (CH₃CN/0.1% H₃PO₄), 4.58 min(96.3%). ¹H NMR (DMSO-d₆) δ 1.92-2.05 (m, 1H, CHH), 2.33-2.48 (m, 1H,CHH), 2.53-2.65 (m, 1H, CHH), 2.83-3.00 (m, 1H, CHH), 4.17-4.48 (m, 2H,CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.28 (s, 2H, CH₂), 5.91 (s,2H, CH₂), 7.27-7.37 (m, 2H, Ar), 7.43-7.52 (m, 1H, Ar), 7.54-7.64 (m,4H, Ar), 7.64-7.72 (m, 1H, Ar), 8.08-8.18 (m, 1H, Ar), 8.39-8.50 (m, 2H,Ar), 8.77-8.92 (m, 3H, Ar), 9.33 (d, J=6.8 Hz, 2H, Ar), 10.99 (br. s.,1H, NH). ¹³C NMR (DMSO-d₆) δ 22.38, 31.18, 45.03, 51.58, 62.47, 68.94,114.97, 115.36, 123.50, 124.75, 126.66, 128.41, 128.92, 129.82, 129.94,133.34, 134.04, 137.93, 138.21, 145.31, 149.68, 150.64, 153.22, 153.30,164.91, 167.93, 170.95, 172.82. LC/MS m/e=519, 520. Anal Calcd forC₃₁H₂₇N₄O₄ ⁺.HCOO⁻: C, 68.08; H, 5.00; N, 9.92; Found: C, 61.92; H,5.05; N, 8.98.

5.942-(2,6-DIOXOPIPERIDIN-3-YL)-4-((4-((2-(TRIFLUOROMETHYL)-5,6-DIHYDROIMIDAZO[1,2-A]PYRAZIN-7(8H)-YL)METHYL)BENZYL)OXY)ISOINDOLINE-1,3-DIONE

To a mixture of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(250 mg, 0.547 mmol) and2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinehydrochloride (137 mg, 0.601 mmol) in dry MeCN (10 mL), was added DIEA(0.334 mL, 1.914 mmol) and the resulting slurry was stirred at roomtemperature for 3 days. Water was added in portions (˜35 mL total) toform a precipitate. The mixture was extensively sonicated with gentlewarming and then stirred for several hours at room temperature until afinely dispersed solid was obtained. The mixture was filtered on amedium fritted funnel and the cake was washed with additional water (˜50mL), suction dried, and placed in a vacuum oven at 50° C. overnight togive to give2-(2,6-dioxopiperidin-3-yl)-4-((4-((2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)benzyl)-oxy)isoindoline-1,3-dioneas a light tan solid (275 mg, 89% yield): HPLC: Waters Symmetry C₁₈, 5Lm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 4.44 min(97.2%); mp: 178-180° C.; ¹H NMR (DMSO-d₆) δ 1.95-2.14 (m, 1H, CHH),2.42-2.66 (m, 2H, CHH, CHH), 2.80-2.99 (m, 3H, CH₂, CHH), 3.62 (s, 2H,CH₂), 3.74 (s, 2H, CH₂), 4.02 (t, J=5.4 Hz, 2H, CH₂), 5.09 (dd, J=5.3,12.8 Hz, 1H, CH), 5.37 (s, 2H, CH₂), 7.35-7.44 (m, 2H, Ar), 7.49 (t, 3H,Ar), 7.61 (d, J=8.5 Hz, 1H, Ar), 7.73 (d, J=1.1 Hz, 1H, Ar), 7.83 (dd,J=7.4, 8.5 Hz, 1H, Ar), 11.11 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.95,30.90, 44.10, 48.37, 48.73, 50.63, 60.16, 69.89, 115.51, 116.58, 119.35,119.40, 120.19, 123.98, 127.38, 128.92, 133.24, 135.15, 136.99, 137.31,144.00, 155.49, 165.27, 166.75, 169.87, 172.72. Not all Ar carbonsignals are observed due to splitting with Fluorine; LCMS: MH=568; AnalCalcd for C₂₈H₂₄F₃N₅O₅+0.2H₂O: C, 58.89; H, 4.31; N, 12.26; F, 9.98;Found: C, 58.91; H, 3.99; N, 11.91; F, 9.37.

5.953-(1-OXO-4-((4-((2-(TRIFLUOROMETHYL)-5,6-DIHYDROIMIDAZO[1,2-A]PYRAZIN-7(8H)-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a suspension of(S)-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.451 mmol) and2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinehydrochloride (113 mg, 0.496 mmol) in dry MeCN (5 mL), was added DIEA(0.276 mL, 1.579 mmol). The resulting solution was stirred for 3 days atroom temperature and then heated to 50° C. for 16 h. The reactionmixture was diluted with water (˜35 mL) and the precipitated solid wasextensively sonicated at 50° C. to help break up solid aggregates. Theresulting slurry was filtered and the solid was washed with additionalwater (˜50 mL) and Et₂O (˜50 mL). The solid was again washed with water(˜75 mL) and Et₂O (˜30 mL) amd then dried in a vacuum oven at 50° C.overnight to give3-(1-oxo-4-((4-((2-(trifluoromethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dioneas a tan solid (189 mg, 76% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 6.99 min (95.8%);mp: 148-150° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.09 (m, 1H, CHH), 2.35-2.48(m, 1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.80-3.06 (m, 3H, CH₂, CHH), 3.61(s, 2H, CH₂), 3.73 (s, 2H, CH₂), 4.02 (t, J=5.4 Hz, 2H, CH₂), 4.26 (d,J=17.4 Hz, 1H, CHH), 4.44 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2Hz, 1H, CH), 5.25 (s, 2H, CH₂), 7.30-7.37 (m, 2H, Ar), 7.37-7.45 (m, 2H,Ar), 7.45-7.56 (m, 3H, Ar), 7.73 (d, J=1.3 Hz, 1H, Imidazole), 10.97 (s,1H, NH); 13C NMR (DMSO-d₆) δ 22.33, 31.16, 44.10, 45.07, 48.44, 50.55,51.55, 60.18, 69.36, 114.96, 115.23, 123.98 (q, J=266.3 Hz, CF₃), 119.37(q, J=4.4 Hz, CCF₃), 127.79, 128.93 (q, J=37.4 Hz, CCF₃), 128.90,129.80, 129.93, 133.30, 135.63, 137.31, 143.99, 153.48, 167.97, 170.96,172.81. Quartets at 119.37 and 127.79 are incomplete; LCMS: MH=554; AnalCalcd for C₂₈H₂₆F₃N₅O₄+0.58H₂O: C, 59.63; H, 4.85; N, 12.42; F, 10.11;Found: C, 59.25; H, 4.46; N, 12.41; F, 10.85.

5.96 3-(1-OXO-4-((4-((3-PROPOXYAZETIDIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE HYDROCHLORIDE

To a solution of(S)-3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.451 mmol) in dry MeCN (5 mL), was added 3-propoxyazetidinehydrochloride (75 mg, 0.496 mmol) and DIEA (0.276 mL, 1.579 mmol). Themixture was stirred at room temperature for 3 h and LCMS indicatedbenzyl bromide starting material was consumed. The mixture was heated to50° C. for ˜30 min, cooled slowly to rt, and then stored at 4° C.overnight. The mixture containing the crude product was concentrated invacuo and the residue was dissolved in minimal DMF (˜5 mL) for Prep HPLCpurification. The product was eluted with an acetonitrile/water gradient(0.1% formic acid in both mobile phases, 5% to 60% MeCN over 20 minutes)and fractions were collected by mass trigger. The desired fractions werecombined and concentrated in vacuo to give a clear glass residue. 1 NHCl (2-3 mL) was added and the mixture was concentrated in vacuo todryness. This process was repeated twice to obtain HCl salt. To theclear residue, MeCN and Et₂O were added in small portions and themixture was sonicated until a white solid was obtained. The slurry wasconcentrated in vacuo to dryness and twice evaporated from Et₂O (3-4 mLportions) until a free flowing white solid was obtained. The solid wasdried in a vacuum oven overnight to give3-(1-oxo-4-((4-((3-propoxyazetidin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dionehydrochloride as a white solid (52 mg, 22%): HPLC: Waters Symmetry C₁₈,5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 6.60 min(99.8%); mp: 142-144° C.; ¹H NMR (DMSO-d₆) 0.87 (t, J=7.4 Hz, 3H, CH₃),1.40-1.59 (m, 2H, CH₂), 1.91-2.06 (m, 1H, CHH), 2.35-2.47 (m, 1H, CHH),2.53-2.65 (m, 1H, CHH), 2.84-3.01 (m, 1H, CHH), 3.28-3.39 (m, 2H, CH₂O,overlapped with DMSO), 3.89 (br. s., 2H, CH₂), 4.06-4.23 (m, 2H, CH₂),4.23-4.32 (m, 2H, CHH, CHH), 4.36 (s, 2H, CH₂), 4.44 (d, J=17.6 Hz, 1H,CHH), 5.12 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.28 (s, 2H, CH₂), 7.27-7.38(m, 2H, Ar), 7.44-7.53 (m, 1H, Ar), 7.55 (s, 4H, Ar), 10.97 (s, 1H, NH),11.09 (br. s., 1H, HCl); ¹³C NMR (DMSO-d₆) δ −0.01, 12.34, 24.22, 32.97,47.32, 53.70, 62.70, 63.30, 69.33, 71.21, 71.67, 117.13, 117.29, 129.67,130.77, 131.82, 131.96, 134.99, 137.66, 138.23, 155.27, 170.35, 172.81,174.98; LCMS: MH=478; Anal Calcd for C₂₇H₃₁N₃O₅.+3.2H₂O+1.3 HCl: C,55.66; H, 6.70; N, 7.21; Cl, 7.91; H₂O, 9.89; Found: C, 53.73; H, 6.33;N, 6.90; Cl, 7.63; H₂O, 9.62.

5.97 ((S)-3-(4-((4-(((3S,5S)-3,5-DIMETHYLMORPHOLINO)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE HYDROCHLORIDE

To a suspension of(S)-3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(250 mg, 0.564 mmol) in MeCN (5 mL), was added(3S,5S)-3,5-dimethylmorpholine (71.4 mg, 0.620 mmol). The mixture wasstirred and sonicated briefly to give a clear solution then DIEA (0.197mL, 1.128 mmol) was immediately added and the resulting mixture wasstirred at room temperature for 2 days. The reaction mixture wasconcentrated in vacuo and the oily residue was partitioned between EtOAc(150 mL) and 1N NaHCO₃ (30 mL). The organic layer was washed with brine,dried (Na₂SO₄), and concentrated in vacuo to give a white solid. Thesolid was dissolved in DMF (8 mL) and purified using reversed-phasepreparatory HPLC. The product was eluted with an acetonitrile/watergradient (0.1% formic acid in both mobile phases, 5% to 50% MeCN over 20minutes) and fractions were collected by mass trigger. The desiredfractions were combined and concentrated in vacuo. 1N HCl (8 mL) wasadded to the concentrate and all solvents were evaporated to give agummy solid. The solid was redissolved in minimal water, frozen andlyophilized to give((S)-3-(4-((4-(((3S,5S)-3,5-dimethylmorpholino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride as a white fluffy solid (160 mg, 55% yield): HPLC: WatersSymmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 5% grad 95% in 10 min,CH₃CN/0.1% H₃PO₄, 5.89 min (97.0%); mp: 230-232; ¹H NMR (DMSO-d₆) δ 1.28(d, J=6.8 Hz, 3H, CH₃), 1.38 (d, J=6.2 Hz, 3H, CH₃), 1.86-2.08 (m, 1H,CHH), 2.36-2.48 (m, 1H, CHH), 2.58 (d, J=17.4 Hz, 1H, CHH), 2.80-3.01(m, 1H, CHH), 3.03-3.22 (m, 1H, CH), 3.48-3.84 (m, 3H, CH₂, CH), 3.91(dd, J=3.2, 12.3 Hz, 1H, CHH), 3.98-4.18 (m, 2H, CHH, CHH), 4.29 (d,J=17.4 Hz, 1H, CHH), 4.45 (d, J=17.6 Hz, 1H, CHH), 4.72 (dd, J=3.8, 13.6Hz, 1H, CHH), 5.12 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.29 (s, 2H, CH₂),7.28-7.41 (m, 2H, Ar), 7.45-7.54 (m, 1H, Ar), 7.58 (d, J=8.1 Hz, 2H,Ar), 7.83 (d, J=8.1 Hz, 2H, Ar), 10.97 (s, 1H, NH), 11.40 (dd, J=1.2,3.1 Hz, 1H, HCl); ¹³C NMR (DMSO-d₆) δ 9.35, 11.92, 22.27, 31.09, 44.99,51.38, 51.49, 53.34, 67.65, 67.88, 68.90, 114.89, 115.30, 127.81,129.25, 129.75, 129.89, 130.93, 133.27, 137.63, 153.29, 167.87, 170.89,172.76; LCMS: MH=478; Anal Calcd for C₂₇H₃₁N₃O₅.+1.3H₂O+2 HCl: C, 56.46;H, 6.25; N, 7.31; Found: C, 56.55; H, 5.93; N, 7.33.

5.98 3-{4-[4-(2-OXA-6-AZA-SPIROI3.31HEPT-6-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the dichloromethane (10 ml) suspension of2-oxa-6-azaspiro[3.3]heptane oxalate (0.124 g, 0.857 mmol) was addedN-ethyl-N-isopropylpropan-2-amine (0.425 ml, 2.57 mmol). The mixture wasstirred at room temperature for 5 min. Then3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.380 g, 0.857 mmol) was added, which was still a suspension. About 3ml of acetonitrile was added and the mixture was stirred at roomtemperature overnight. The mixture was purified by preparative HPLC(MeCN/water in 0.1% HCOOH) to give3-{4-[4-(2-Oxa-6-aza-spiro[3.3]hept-6-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione(39 mg, 10% yield); mp, not determined. HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 90/10 in 5min, isocratic at 90/10 in 5 min (CH₃CN/0.1% H₃PO₄), 4.32 min (95.2%).¹H NMR (DMSO-d₆) δ 1.93-2.04 (m, 1H, CHH), 2.36-2.48 (m, 1H, CHH),2.53-2.64 (m, 1H, CHH), 2.84-2.99 (m, 1H, CHH), 3.30 (s, 3H, CH₂CH₂),3.51 (s, 1H, CH₂), 4.20-4.47 (m, 2H, CH₂), 4.59 (s, 3H, CH₂CH₂), 5.11(dd, J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 1H, CH₂), 7.23-7.36 (m, 4H, Ar),7.38-7.53 (m, 3H, Ar), 10.97 (br. s., 1H, NH). ¹³C NMR (DMSO-d₆) δ22.39, 31.21, 38.54, 45.13, 51.66, 61.97, 62.85, 69.47, 79.96, 115.05,115.26, 127.62, 128.35, 129.79, 130.00, 133.35, 135.23, 137.96, 153.51,167.99, 170.92, 172.76. LC/MS m/e=462.

5.993-(1-OXO-4-{4-[2-(TETRAHYDRO-PYRAN-4-YL)-ETHYL]-BENZYLOXY}-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: Preparation of 4-[2-(Tetrahydro-pyran-4-yl)-vinyl]-benzoic acidmethyl ester

Sodium hydride (60% in oil) (0.378 g, 9.46 mmol) was added into astirred solution of anhydrous DMSO (50 ml). The mixture was stirred atroom temperature for 20 min. Added(4-Methoxycarbonylbenzyl)triphenylphosphonium bromide (4.65 g, 9.46mmol) (white powder) to the mixture in an 5˜12° C. cold water bath.After two hours, tetrahydro-2H-pyran-4-carbaldehyde (0.9 g, 7.88 mmol)was added. The mixture was stirred at room temperature for two days.Water (50 ml) was added to the mixture, and was extracted with ethylacetate (2×30 ml), washed with brine (50 ml), dried and concentrated toan oily solid, which was purified by silica gel column (EtOAc/Hexanes)to give 4-[2-(tetrahydro-pyran-4-yl)-vinyl]-benzoic acid methyl ester asa white solid (1.2 g, 61% yield). LC/MS m/e=247. The product was used inthe next step without further purification.

Step 2: Preparation of 4-[2-(tetrahydro-pyran-4-yl)-ethyl]-benzoic acidmethyl ester

A mixture of 4-[2-(tetrahydro-pyran-4-yl)-vinyl]-benzoic acid methylester (1.36 g, 5.52 mmol) and palladium on activated carbon 10 wt % (50%wet) (0.21 g, 8.92 mmol) in methanol (50 ml) was hydrogenated with ahydrogen balloon at room temperature overnight. The black suspension wasfiltered through Celite, the filtrate was evaporated to give4-[2-(tetrahydro-pyran-4-yl)-ethyl]-benzoic acid methyl ester as a whitesolid (1.33 g, 97% yield). LC/MS m/e=217. It was used in the next stepwithout further purification.

Step 3: Preparation of{4-[2-(tetrahydro-pyran-4-yl)-ethyl]-phenyl}-methanol Lithium AluminumHydride (2.0M in THF) (2.29 ml, 4.58 mmol) was added dropwise to astirred solution of 4-[2-(tetrahydro-pyran-4-yl)-ethyl]-benzoic acidmethyl ester (0.64 g, 2.58 mmol) in tetrahydrofuran (8 ml) in anice-bath at 0° C. The mixture was stirred at 0° C. for 30 min, thesolution was cooled in an ice-bath and added water dropwise to form awhite gel, gas was evolved out. More water (30 ml) was added. It wasextracted with EtOAc (3×30 ml) and separated the two phases by adding“1N Rochelle salt solution”. The organic phase was evaporated to give{4-[2-(tetrahydro-pyran-4-yl)-ethyl]-phenyl}-methanol as a white solid(0.58 g, 102% crude yield). LC/MS m/e=203. It was used in the next stepwithout further purification.

Step 4: Preparation of4-[2-(4-Bromomethyl-phenyl)-ethyl]-tetrahydro-pyran

To a stirred slurry of(4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)phenyl)methanol (0.57 g, 2.59mmol) in dry MeCN (8 mL) at 0° C., was added tribromophosphine (0.466ml, 4.94 mmol). The resulting mixture was stirred at 0° C. for 20minutes, then allowed to warm up to room temperature. The cloudysuspension was quenched with water (˜5 ml) in an ice-bath, added morewater (20 ml), extracted with ethyl acetate (2×30 ml). The combinedorganic phases were washed with brine (20 ml), dried over sodium sulfateand concentrated to give4-[2-(4-Bromomethyl-phenyl)-ethyl]-tetrahydro-pyran as an oil (0.74 g,101% crude yield). It was used in the next step without furtherpurification.

Step 5: Preparation of4-Carbamoyl-4-(-oxo-4-{4-[2-(tetrahydro-pyran-4-yl)-ethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-butyricacid methyl ester

A white suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.764 g,2.61 mmol), 4-(4-(bromomethyl)phenethyl)tetrahydro-2H-pyran (0.74 g,2.61 mmol), and potassium carbonate (0.361 g, 2.61 mmol) in acetonitrile(15 ml) was stirred in a 50° C. oil bath overnight. The white suspensionwas filtered, and the filtrate was evaporated to a white solid, whichwas purified by silica gel column (MeOH/CH₂Cl₂) to give4-Carbamoyl-4-(1-oxo-4-{4-[2-(tetrahydro-pyran-4-yl)-ethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-butyricacid methyl ester as a white solid (0.96 g, 74% yield). LC/MS m/e=495.It was used in the next step without further purification.

Step 6: Preparation of3-(1-Oxo-4-{4-[2-(tetrahydro-pyran-4-yl)-ethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione

To a stirred solution of methyl5-amino-5-oxo-4-(1-oxo-4-(4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)benzyloxy)isoindolin-2-yl)pentanoate(0.96 g, 1.941 mmol) in tetrahydrofuran (10 ml) at 0° C. in an ice-bathwas added potassium 2-methylpropan-2-olate (0.218 g, 1.941 mmol). Themixture was stirred for ten minutes then quenched with 1 N HCl (topH=1), neutralized with saturated sodium bicarbonate to pH=7, extractedwith methylene chloride (3×30 ml). The combined methylene chloridephases were washed with (2×20 ml), dried and concentrated to a whitesolid. It was stirred in ether (20 ml) for a couple of hours, andfiltered to give3-(1-Oxo-4-{4-[2-(tetrahydro-pyran-4-yl)-ethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (0.64 g, 71% yield); mp, 254-256° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 90/10 in 5 min, isocratic at 90/10 in 5 min (CH₃CN/0.1% H₃PO₄), 7.18min (96.7%). ¹H NMR (DMSO-d₆) δ 1.13-1.28 (m, 2H, CH₂), 1.45-1.54 (m,3H, CH₂, CH), 1.61 (d, J=13.0 Hz, 2H, CH₂), 1.87-2.09 (m, 1H, CHH),2.33-2.44 (m, 1H, CHH), 2.60 (t, J=7.6 Hz, 3H, CH₂, CHH), 2.91 (br. s.,1H, CHH), 3.24 (td, J=1.7, 11.6 Hz, 2H, CH₂), 3.82 (dd, J=3.0, 11.1 Hz,2H, CH₂), 4.14-4.48 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH),5.20 (s, 2H, CH₂), 7.22 (d, J=8.1 Hz, 2H, Ar), 7.31-7.67 (m, 5H, Ar),10.96 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 522.36, 31.21, 31.63, 32.64,33.89, 38.24, 45.10, 51.59, 67.03, 69.49, 115.01, 115.20, 127.85,128.34, 129.79, 129.97, 133.31, 133.86, 142.20, 153.53, 168.01, 170.96,172.82. LC/MS m/e=463. Anal Calcd for C₂₇H₃₀N₂O₅ (+0.1H₂O): C, 69.84; H,6.56; N, 6.03; Found: C, 69.57; H, 6.64; N, 5.93.

5.100 2-(2, 6-DIOXOPIPERIDIN-3-YL)-4-((6-(MORPHOLINOMETHYL)IMIDAZO[1,2-A]PYRIDINE-2-YL)METHOXY)ISOINDOLINE-1,3-DIONE

Step 1: A mixture of 3-hydroxyphthalic anhydride (1.6 g, 9.8 mmol) inmethanol (25 mL) was refluxed for 3 h. The mixture was cooled andconcentrated. Residue and NaHCO₃ (2.3 g, 27.3 mmol) were stirred in DMF(20 mL). Iodomethane (3.3 g, 23.4 mmol) was added and reaction mixturewas heated at 50° C. oil bath for 3 h. The reaction mixture was cooledand diluted with EtOAc (80 mL) and water (40 mL). The mixture wasacidified with 4N HCl and aq. layer was extracted with EtOAc (2×40 mL).Combined EtOAc solution was washed with water (2×40 mL), brine (40 mL)and dried. Solvent was removed and residue was purified bychromatography (SiO₂, 10% EtOAc/hexane for 15 min then to 20% over 5 minand hold for 15 min then to 30% over 5 min and hold for 15 min) to givedimethyl 3-hydroxyphthalate (1.8 g, 89%): ¹H NMR (CDCl₃) δ 3.89 (s, 3H),3.92 (s, 3H), 6.95-6.98 (dd, J=3 and 9 Hz, 1H), 7.06-7.10 (dd, J=3 and 9Hz, 1H), 7.41-7.48 (t, J=9 Hz, 1H), 10.55 (s, 1H); ¹³C NMR (CDCl₃) δ52.64, 52.90, 110.19, 119.11, 119.83, 134.58, 135.46, 161.08, 169.33,169.39.

Step 2: A mixture of ethyl 6-aminonicotinate (5.0 g, 30.1 mmol) and1,3-dichloropropan-2-one (5.7 g, 45.1 mmol) in acetonitrile (100 mL) wasrefluxed for 17 h. The mixture was concentrated and residue was stirredwith CH₂Cl₂ (100 mL) and sat. NaHCO₃ (35 mL). The organic layer waswashed with brine (40 mL) and dried. Solvent was removed and residue waspurified by chromatography (SiO₂, 30% EtOAc/CH₂Cl₂ for 25 min then to100% EtOAc over 15 min) to give ethyl2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (4.7 g, 65%): ¹HNMR (CDCl₃) δ 1.42 (t, J=6 Hz, 3H), 4.38-4.45 (q, J=6 Hz, 2H), 4.77 (s,2H), 7.56-7.59 (d, J=9 Hz, 1H), 7.74-7.77 (dd, J=3 and 9 Hz, 1H),8.86-8.87 (d, J=3 Hz, 1H).

Step 3: A solution of ethyl2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboxylate (2.1 g, 8.8 mmol)in anhydrous CH₂Cl₂ (60 mL) was cooled in dry ice/acetone bath. Asolution of diisobutylaluminum hydride/CH₂Cl₂ (1M, 26.4 mL, 26.4 mmol)was added slowly at −70° C. After addition, reaction mixture was stirredat −70° C. for 1.5 h then quenched with methanol (5 mL). The mixture wasdiluted with CH₂Cl₂ (40 mL), and sat. NaHCO₃ (40 mL) and warmed to roomtemperature. The mixture was filtered and washed solid with CH₂Cl₂ (50mL). Layers were separated and organic layer was washed with water (35mL), brine (35 mL) and dried. Solvent was removed to give2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboaldehyde (1.5 g, 89%),which was used in next step without purification.

Step 4: A solution of2-(chloromethyl)imidazo[1,2-a]pyridine-6-carboaldehyde (1.5 g, 7.9mmol), morpholine (0.7 g, 7.9 mmol) and acetic acid (0.6 g, 9.4 mmol) inTHF (60 mL) was stirred at room temperature for 15 min. Sodiumtriacetoxyborohydride (3.3 g, 15.7 mmol) was added and mixture wasstirred at room temperature for 1 h, Reaction mixture was diluted withCH₂Cl₂ (50 mL) and cooled in ice bath and quenched with sat. NaHCO₃ (40mL). The organic layer was washed with brine (30 mL) and dried. Solventwas removed and residue was purified by chromatography (SiO₂, CH₂Cl₂ for5 min then to 3% CH₃OH/CH₂Cl₂ over 5 min and hold for 15 min then to 5%over 5 min and hold for 15 min) to give4-((2-(chloromethyl)imidazo[1,2-a]pyridine-6-yl)methyl)morpholine (1.1g, 53%): ¹H NMR (CDCl₃) δ 2.45-2.49 (m, 4H), 3.47 (s, 2H), 3.70-3.73 (m,4H), 4.76 (s, 2H), 7.22-7.25 (dd, J=3 and 9 Hz, 1H), 7.53-7.57 (m, 2H),8.03 (s, 1H).

Step 5: A mixture of4-((2-(chloromethyl)imidazo[1,2-a]pyridin-6-yl)methyl)morpholine (1.1 g,4.2 mmol), dimethyl 3-hydroxyphthalate (0.9 g, 4.2 mmol) and potassiumcarbonate (0.6 g, 4.2 mmol) in DMF (20 mL) was heated at 55° C. oil bathfor 7 h. The reaction mixture was cooled and diluted with EtOAc (100 mL)and washed with water (3×30 mL), brine (30 mL) and dried. Solvent wasremoved and residue was purified by chromatography (SiO₂, CH₂Cl₂ for 5min then to 3% CH₃OH/CH₂Cl₂ over 5 min and hold for 15 min then to 5%over 5 min and hold for 15 min) to give dimethyl3-((6-(morpholinomethyl)imidazo[1,2-a]pyridine-2-yl)methoxy)phthalate(0.6 g, 32%): ¹H NMR (CDCl₃) δ 2.43-2.45 (m, 4H), 3.45 (s, 2H),3.70-3.73 (m, 4H), 3.89 (s, 3H), 3.91 (s, 3H), 5.39 (s, 2H), 7.19 (m,1H), 7.30-7.38 (m, 2H), 7.45-7.61 (m, 3H), 8.01 (s, 1H).

Step 6: Sodium hydroxide (0.3 g, 6.5 mmol) was added to a stirredsolution of dimethyl3-((6-(morpholinomethyl)imidazo[1,2-a]pyridin-2-yl)methoxy)phthalate(1.0 g, 2.3 mmol) in ethanol (20 mL). The resulting mixture was refluxedfor 1 h then cooled and neutralized with acetic acid (0.5 g, 8.3 mmol).The mixture was concentrated and residue was dissolved in pyridine (30mL). To this solution was added α-aminoglutarimide hydrochloride (0.4 g,2.3 mmol) and the resulting mixture was refluxed for 5 h. The reactionmixture was cooled and concentrated. Residue was stirred with EtOAc (50mL) and water (30 mL). The mixture was filtered and solid was washedwith EtOAc (20 mL). Layers were separated and aq. layer was extractedwith EtOAc (2×40 mL). Combined EtOAc solution was washed with water(2×30 mL), brine (30 mL) and dried. Solvent was removed and residue waspurified by chromatography (SiO₂, CH₂Cl₂ for 5 min then to 3%CH₃OH/CH₂Cl₂ over 5 min and hold for 10 min then to 5% over 5 min andhold for 15 min) to give2-(2,6-dioxopiperidin-3-yl)-4-((6-(morpholinomethyl)imidazo[1,2-a]pyridin-2-yl)methoxy)isoindoline-1,3-dione(0.12 g, 10%): mp 255-257° C.; ¹H NMR (DMSO-d₆) δ 1.99-2.05 (m, 1H),2.36-2.39 (m, 4H), 2.54-2.61 (m, 2H), 2.85-2.89 (m, 1H), 3.44-3.58 (m,6H), 5.05-5.11 (dd, J=6 and 15 Hz, 1H), 5.46 (s, 2H), 7.22-7.25 (dd, J=3and 6 Hz, 1H), 7.45-7.49 (m, 2H), 7.73-7.82 (m, 2H), 8.01 (s, 1H), 8.47(s, 1H), 11.11 (s, 1H); ¹³C NMR (DMSO-d₆) δ 21.95, 30.89, 48.72, 52.97,59.11, 65.32, 66.13, 111.95, 115.41, 116.24, 115.40, 120.31, 122.31,125.79, 127.03, 133.21, 136.87, 141.13, 143.91, 155.55, 165.24, 166.76,169.87, 172.74; Calcd for C₂₆H₂₅N₅O₆+0.9H₂O: C, 60.09; H, 5.20; N,13.47; Found: C, 60.05; H, 5.01; N, 13.22.

5.1013-{4-[4-(1,4-DIHYDRO-OUINAZOLIN-2-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: (4-Bromomethyl-phenyl)-acetic acid tert-butyl ester

The stirred solution of 2-(4-(bromomethyl)phenyl)acetic acid (2.6 g,11.35 mmol) in thionyl chloride (20 mL, 274 mmol) was heated to refluxfor 2.5 hrs. The reaction mixture was concentrated under vacuo to giveoff white solid. The white solid was added to the stirred solution of2-methylpropan-2-ol (20 ml, 213 mmol) in DCM (2 mL) under ice/waterbath. And the mixture was stirred under ice/water bath for 2 hrs and atroom temperature for 18 hrs. The reaction mixture was added to CH₂Cl₂(40 mL). The organic phase was washed successively with H₂O (20 mL),NaHCO₃ (sat, aq, 20 mL), and brine (25 mL) and dried over MgSO₄. Organiclayer was concentrated under vacuo to give (4-bromomethyl-phenyl)-acetic acid tert-butyl ester as a light yellow liquid(2.4 g, 74% crude yield). 1H NMR (DMSO-d6): 1.39 (s, 9H, tBu), 3.54 (s,2H, CH2CO2), 4.69 (s, 2H, CH2Br), 7.23, 7.39 (m, 4H, due to impurities).

Step 2:4-[4-(4-tert-Butoxycarbonylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester

To the stirred mixture of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.5 g, 5.13mmol) and tert-butyl 2-(4-(bromomethyl)phenyl)acetate (2.2 g, 7.7 mmol)in Acetonitrile (30 mL) was added POTASSIUM CARBONATE (1.42 g, 10.3mmol). The resulting reaction mixture was stirred at 50° C. for 27 hrsand in between tert-butyl 2-(4-(bromomethyl)phenyl)acetate (800 mg, 2.9mmol) was added in 2 portions. The reaction mixture was filtered and thelight brown solid was washed with acetonitrile (2×20 mL). The filtratewas concentrated under vacuo and the residue was purified by ISCO4-[4-(4-tert-Butoxycarbonylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as a light yellow sticky solid (2.1 g, 82% crudeyield) LCMS MH=497.

Step 3:4-Carbamoyl-4-[4-(4-carboxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

To the stirred solution of methyl5-amino-4-(4-(4-(2-tert-butoxy-2-oxoethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(2.1 g, 4.2 mmol) in DCM (20 mL) at room temperature was added by WATER(0.38 ml, 21.1 mmol) followed by the addition of TFA (1.63 ml, 21.1mmol) slowly. The resulting solution was stirred at room temperature for5 hrs and in between TFA (3.2 mL) and water (0.15 mL) were added. Themixture was kept in fridge overnight and the reaction mixture wasconcentrated under vacuo to give 4-Carbamoyl-4-[4-(4-carboxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acid methylester as an off white solid (2.3 g, 123% crude yield). ¹H NMR (DMSO-d₆)δ 1.97-2.31 (m, 4H, CH₂, CH₂), 3.50 (s, 3H, CH₃), 3.58 (s, 2H, CH₂),4.41 (d, J=17.8 Hz, 1H, CHH), 4.53 (d, J=17.8 Hz, 1H, CHH), 4.72 (dd,J=4.6, 10.3 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 7.18 (br. s., 1H, NHH),7.24-7.34 (m, 4H, Ar), 7.40-7.50 (m, 3H, Ar), 7.57 (br. s., 1H, NHH);LCMS MH=441.

Step 4: 5-amino-4-(4-(4-(2-(2-aminobenzylamino)-2-oxoethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate

To the stirred solution of2-(4-((2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)phenyl)aceticacid (820 mg, 1.9 mmol) in DMF (10 mL at room temperature was added HOBT(285 mg, 1.9 mmol). A minute later, 2-(aminomethyl)aniline (227 mg, 1.9mmol), EDC (357 mg, 1.9 mmol) and DIEA (0.81 ml, 4.65 mmol) were added.

The resulting solution was stirred at room temperature for 17 hrs beforeit was added by water (40 mL) and EtOAc (60 mL). The mixture wasextracted and the aq layer was extracted with EtOAc (50 mL). The organiclayers were combined, dried by MgSO₄ and concentrated under vacuo. Theresidue was purified by ISCO to give 5-amino-4-(4-(4-(2-(2-aminobenzylamino)-2-oxoethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas a sticky oil (300 mg, 30% yield). The compound was put to next stepwithout further purification. LCMS MH=545.

Step 5: Methyl5-amino-4-(4-((4-(2-((2-aminobenzyl)amino)-2-oxoethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate

The solution of methyl5-amino-4-(4-(4-(2-(2-aminobenzylamino)-2-oxoethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg, 0.55 mmol) in ACETICACID (4 ml, 69.9 mmol) was heated at microwave oven at 125° C. for 10mins. The reaction mixture was added to NaHCO₃ (aq, sat, 50 mL) slowlyto control the formation of CO₂. The resulting mixture was extractedwith DCM (100 mL). Organic layer was washed with NaHCO₃ (aq, sat, 15 mL)and brine (20 mL). Organic layer was dried by MgSO₄ and concentratedunder vacuo to give methyl5-amino-4-(4-((4-(2-((2-aminobenzyl)amino)-2-oxoethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas a light brown solid (240 mg, 83% yield); ¹H NMR (DMSO-d₆) δ 2.00-2.31(m, 4H, CH₂, CH₂), 3.46 (s, 2H, CH₂), 3.49 (s, 3H, CH₃), 4.33-4.57 (m,4H, CHH, CHH, CH₂), 4.71 (dd, J=4.8, 10.3 Hz, 1H, CHH), 5.21 (s, 2H,CH₂), 6.75 (d, J=7.7 Hz, 1H, Ar), 6.88 (d, J=4.2 Hz, 2H, Ar), 7.00-7.13(m, 1H, Ar), 7.13-7.23 (m, 1H, NHH), 7.23-7.33 (m, 2H, Ar), 7.33-7.49(m, 6H, Ar), 7.57 (s, 1H, NHH); LCMS MH=527.

Step 6:3-{4-[4-(1,4-Dihydro-quinazolin-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred suspension of methyl5-amino-4-(4-(4-((1,4-dihydroquinazolin-2-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(240 mg, 0.46 mmol) in Tetrahydrofuran (10 mL) at 0° C. (ice/water bath)was added POTASSIUM TERT-BUTOXIDE (56.3 mg, 0.5 mmol). The resultingmixture was stirred at 0° C. for 2 hrs and KOtBu (37 mg, 0.33 mmol) wasadded to the reaction mixture for further reaction at 0° C. 1.5 hrslater, the reaction mixture was diluted by DCM (50 mL) followed by theaddition of HCl (2 mL, 1N, aq). The mixture was stirred for 1 min andNaHCO₃ (aq, sat., 20 mL) was added. The mixture was filtered to get someyellow solid. The filtrate was extracted and aq layer was extracted withDCM (30 mL). Combined organic layers were dried by MgSO₄ and filtered.The filtrate was concentrated and the residue was purified by ISCO togive3-{4-[4-(1,4-Dihydro-quinazolin-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (25 mg, 11% yield); HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, 23/77, (CH₃CN/0.1% H₃PO₄), 3.90 min (96.3%);mp: 153-155° C. (in house); ¹H NMR (DMSO-d₆) δ 1.98 (br. s., 1H, CHH),2.35-2.46 (m, 1H, CHH), 2.54-2.62 (m, 1H, CHH), 2.87 (dd, J=4.7, 12.8Hz, 1H, CHH), 3.45 (s, 2H, CH₂), 4.23 (d, J=17.6 Hz, 1H, CHH), 4.40 (d,J=17.6 Hz, 1H, CHH), 4.48 (s, 2H, CH₂), 5.09 (dd, J=5.1, 13.2 Hz, 1H,CHH), 5.20 (s, 2H, CH₂), 6.74 (d, J=7.7 Hz, 1H, Ar), 6.88 (d, J=4.2 Hz,2H, Ar), 6.99-7.10 (m, 1H, Ar), 7.25-7.56 (m, 8H, Ar, NH), 10.95 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 22.23, 31.09, 40.98, 45.02, 51.48, 69.32,114.83, 115.11, 122.98, 125.44, 127.34, 127.78, 127.88, 128.75, 129.10,129.72, 129.88, 133.22, 134.62, 137.18, 153.41, 167.92, 170.86, 172.73;LCMS MH=495; Anal. Calcd for C₂₉H₂₅N₄O₄: C, 70.43; H, 5.30; N, 11.33;Found: N/A.

5.1023-(1-OXO-4-{4-[2-(TETRAHYDRO-PYRAN-4-YL)-ETHYL]-BENZYLOXY}-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: Preparation of 4-(Tetrahydro-pyran-4-ylidenemethyl)-benzoic acidmethyl ester

Sodium hydride (60% in oil) (0.240 g, 5.99 mmol) was added into astirred solution of anhydrous DMSO (50 ml). The mixture was stirred atroom temperature for 20 minutes. To the mixture was added(4-Methoxycarbonylbenzyl)triphenylphosphonium bromide (2.94 g, 5.99mmol) (white powder) in an 5-12° C. cold water bath. After two hours,dihydro-2H-pyran-4(3H)-one (0.5 g, 4.99 mmol) in DMSO (3 ml) was added.The mixture was stirred at room temperature overnight, then diluted withwater (80 ml) slowly and extracted with ethyl acetate (3×80 ml). Thecombined ethyl acetate phases were further washed with water (2×100 ml).The ethyl acetate phase was evaporated to an off-white solid andpurified by silica gel column (EtOAc/Hexanes) to give4-(Tetrahydro-pyran-4-ylidenemethyl)-benzoic acid methyl ester as an oil(0.74 g, 63% yield). HNMR showed 72% pure. The product was used in thenext step without further purification.

Step 2: Preparation of 4-(Tetrahydro-pyran-4-ylmethyl)-benzoic acidmethyl ester

A mixture of 4-(tetrahydro-pyran-4-ylidenemethyl)-benzoic acid methylester (0.743 g, 3.20 mmol) and palladium on activated carbon 10 wt %(50% wet) (0.14 g, 69.4 mmol) in methanol (30 ml) was hydrogenated withtwo hydrogen balloons for three hours. The suspension was filteredthrough a Celite pad, the filtrate was evaporated to give4-(Tetrahydro-pyran-4-ylmethyl)-benzoic acid methyl ester as an oilysolid (0.71 g, 95% yield). HNMR showed 70% pure. It was used in the nextstep without further purification.

Step 3: Preparation of [4-(Tetrahydro-pyran-4-ylmethyl)-phenyl]-methanolLithium Aluminum Hydride (2.0 M in THF) (1.494 ml, 2.99 mmol) was addeddropwise to a stirred solution of4-(Tetrahydro-pyran-4-ylmethyl)-benzoic acid methyl ester (0.7 g, 2.99mmol) in tetrahydrofuran (8 ml) in an ice-bath at 0° C. The mixture wasstirred for 20 minutes. The solution was cooled in an ice-bath and addedwater (30 ml) dropwise to form a white gel, gas was evolved out. It wasextracted with EtOAc (2×40 ml) and separated the two phases by adding“1N Rochelle salt solution”. The organic phase was evaporated andpurified by silica gel column (EtOAc/Hexanes) to give[4-(Tetrahydro-pyran-4-ylmethyl)-phenyl]-methanol as an oil (0.16 g, 26%yield). It was used in the next step without further purification.

Step 4: Preparation of 4-(4-Bromomethyl-benzyl)-tetrahydro-pyran

To a stirred slurry of(4-((tetrahydro-2H-pyran-4-yl)methyl)phenyl)methanol (0.16 g, 0.776mmol) in acetonitrile (anhydrous) (8 ml, 0.776 mmol) at 0° C., was addedtribromophosphine (0.110 ml, 1.163 mmol). The resulting mixture wasstirred at 0° C. for 10 minutes. The suspension was quenched with water(25 ml) in an ice-bath, extracted with ethyl acetate (2×30 ml). Thecombined org phases were washed with brine (20 ml), dried over sodiumsulfate and concentrated to give4-(4-Bromomethyl-benzyl)-tetrahydro-pyran as an oil (0.206 g, 99% crudeyield). It was used in the next step without further purification.

Step 5: Preparation of4-Carbamoyl-4-{1-oxo-4-[4-(tetrahydro-pyran-4-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester

A white suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.195 g,0.669 mmol), 4-(4-(bromomethyl)benzyl)tetrahydro-2H-pyran (0.18 g, 0.669mmol), and potassium carbonate (0.092 g, 0.669 mmol) in acetonitrile (10ml) was stirred in a 50° C. oil bath overnight. The suspension wasfiltered and the filtrate was evaporated to an oil, which was purifiedby silica gel column (MeOH/CH₂Cl₂) to give4-Carbamoyl-4-{1-oxo-4-[4-(tetrahydro-pyran-4-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as an oil (˜0.15 g, 46% yield). It was used in thenext step without further purification.

Step 6: Preparation of3-{-Oxo-4-[4-(tetrahydro-pyran-4-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To a stirred solution of methyl5-amino-5-oxo-4-(1-oxo-4-(4-((tetrahydro-2H-pyran-4-yl)methyl)benzyloxy)isoindolin-2-yl)pentanoate(0.15 g, 0.312 mmol) in tetrahydrofuran (8 ml) at 0° C. in an ice-bathwas added potassium 2-methylpropan-2-olate (0.035 g, 0.312 mmol). Thesolution was stirred for ten minutes and quenched with 1 N HCl to pH=1then neutralized with saturated sodium bicarbonate to pH=7, andextracted with ethyl acetate (2×30 ml). The EtOAc phases were washedwith water (20 ml), brine (20 ml), dried and concentrated to an oil,which was purified by silica gel column (40 g, MeOH/CH₂Cl₂) to give3-(1-Oxo-4-{4-[2-(tetrahydro-pyran-4-yl)-ethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (64 mg, 46% yield); mp, 172-174° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 90/10 in 5 min, isocratic at 90/10 in 5 min (CH₃CN/0.1% H₃PO₄), 6.88(96.1%). ¹H NMR (DMSO-d₆) δ 1.12-1.29 (m, 2H, CH₂), 1.39-1.53 (m, 2H,CH₂), 1.61-1.82 (m, 1H, CH), 1.91-2.04 (m, 1H, CHH), 2.35-2.48 (m, 1H,CHH), 2.53-2.64 (m, 1H, CHH), 2.83-3.00 (m, 1H, CHH), 3.16-3.28 (m, OH,CH₂), 3.75-3.87 (m, J=0.9, 0.9, 4.7, 11.4 Hz, OH, CH₂), 4.18-4.47 (m,2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.20 (s, 2H, CH₂), 7.20(d, J=7.9 Hz, 2H, Ar), 7.32 (d, J=7.7 Hz, 2H, Ar), 7.40 (d, J=8.1 Hz,2H, Ar), 7.44-7.54 (m, 1H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ22.36, 31.20, 32.46, 36.36, 42.28, 45.09, 51.58, 66.91, 69.48, 114.97,115.20, 127.68, 129.11, 129.81, 129.94, 133.29, 134.04, 139.81, 153.53,168.01, 170.96, 172.82. LC/MS m/e=449. Anal Calcd for C₂₆H₂₈N₂O₅(+0.4H₂O): C, 68.53; H, 6.37; N, 6.15; Found: C, 68.35; H, 6.44; N,6.03.

5.1033-{1-OXO-4-[4-(3-PHENOXY-AZETIDIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.36 g, 0.812 mmol) was added 3-phenoxyazetidine (0.158 g, 1.056 mmol)and N-ethyl-N-isopropylpropan-2-amine (0.268 ml, 1.624 mmol). Thesolution was stirred at room temperature for one hour. Solvent wasevaporated and mixed with methylene chloride (80 ml). It was washed withwater (2×40 ml), dried and concentrated to an oil, which was purified bysolica gel column (MeOH/CH₂Cl₂) to give3-{1-Oxo-4-[4-(3-phenoxy-azetidin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.237 g, 57% yield); mp, 150-152° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 90/10 in 5 min, isocratic at 90/10 for 5 min (CH₃CN/0.1% H₃PO₄), 4.83min (96.0%). ¹H NMR (DMSO-d₆) δ 1.91-2.06 (m, 1H, CHH), 2.36-2.48 (m,1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.83-2.98 (m, 1H, CHH), 3.04 (ddd,J=1.8, 5.3, 6.9 Hz, 2H, CH₂), 3.65 (s, 2H, CH₂), 3.68-3.79 (m, 2H, CH₂),4.19-4.48 (m, 2H, CH₂), 4.80 (quin, J=5.7 Hz, 1H, CH), 5.11 (dd, J=5.1,13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 6.82 (dd, J=1.0, 8.8 Hz, 2H, Ar),6.89-6.98 (m, 1H, Ar), 7.22-7.37 (m, 5H, Ar), 7.40-7.53 (m, 3H, Ar),10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.36, 31.21, 45.10, 51.59,60.56, 62.35, 66.23, 69.41, 114.49, 114.98, 115.23, 120.89, 127.68,128.39, 129.60, 129.81, 129.95, 133.32, 135.23, 138.05, 153.50, 156.68,168.01, 170.96, 172.82. LC/MS m/e=512. Anal Calcd for C₃₀H₂₉N₃O₅(+0.9H₂O): C, 68.27; H, 5.88; N, 7.96; Found: C, 67.93; H, 5.69; N,7.84.

5.1043-(4-{4-[3-(4-FLUORO-PHENOXY)-AZETIDIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONEFORMATE

To a 20-mL reaction vial charged with3-(4-((4-(bromomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300 mg, 0.677 mmol) and 3-(4-fluorophenoxy)azetidine hydrochloride (145mg, 0.711 mmol), was added dry MeCN (10 mL) followed by DIEA (0.355 mL,2.0 mmol). The resulting suspension was warmed to 50° C. to give a clearsolution. After ˜30 min, the temperature was raised further to 70° C.and the reaction mixture was stirred for ˜16 h at 70° C. The reactionmixture was cooled to room temperature and then concentrated undervacuum. The residue was diluted in EtOAc (˜100 mL) and then extractedwith 1N NaHCO₃ (2×35 mL) and brine. Drying (Na₂SO₄) and concentration ona rotovap gave a glassy solid. Et₂O (˜15 mL) was added to the glass insmall portions and with intermittent sonication until a well-dispersedsolid was formed. The slurry was agitated vigorously and then filteredon a 15-mL fine fritted funnel. The solid was dissolved in DMF (7 mL)and purified using reversed-phase preparatory HPLC. The product waseluted with an acetonitrile/water gradient (0.1% formic acid in bothmobile phases, 5% to 95% MeCN over 20 minutes) and fractions werecollected by mass trigger. The desired fractions were combined andconcentrated in vacuo to give3-(4-{4-[3-(4-fluoro-phenoxy)-azetidin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneformate as a white solid (204 mg, 52% yield): HPLC: Waters Symmetry C18,5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 27/73 CH₃CN/0.1% H₃PO₄, 3.62 min(98.4%); mp: 166-168° C.; ¹H NMR (DMSO-d₆) δ 1.88-2.04 (m, 1H, CHH),2.36-2.49 (m, 1H, CHH), 2.52-2.63 (m, 1H, CHH), 2.91 (ddd, J=5.3, 13.5,17.4 Hz, 1H, CHH), 3.03 (dd, J=5.6, 8.2 Hz, 2H, CHH, CHH), 3.64 (s, 2H,CH₂N), 3.71 (dd, J=6.2, 8.3 Hz, 2H, CHH, CHH), 4.25 (d, J=17.4 Hz, 1H,CHH), 4.41 (d, J=17.6 Hz, 1H, CHH), 4.77 (quin, J=5.7 Hz, 1H, OCH), 5.11(dd, J=5.1, 13.2 Hz, 1H, CH), 5.22 (s, 2H, CH₂), 6.75-6.91 (m, 2H, Ar),7.00-7.21 (m, 2H, Ar), 7.28-7.38 (m, 4H, Ar), 7.39-7.62 (m, 3H, Ar),8.16 (s, 1H, HCOOH), 10.97 (s, 1H, NH). ˜1.8 equiv. of HCOOH at 8.16 ppmis observed. ¹³C NMR (DMSO-d₆) δ 22.33, 31.18, 45.07, 51.56, 60.41,62.29, 66.70, 69.36, 114.97, 115.20, 115.70, 115.80, 116.09, 127.66,128.39, 129.78, 129.93, 133.30, 135.24, 137.98, 153.23 (d, J=35.2 Hz,CF), 158.22, 163.15, 167.97, 170.95, 172.80; LCMS: MH=530; Anal Calcdfor C₃₀H₂₈FN₃O₅+1.8 HCOOH+1.25H₂O: C, 60.16; H, 5.41; N, 6.62; Found: C,60.08; H, 5.05; N, 6.56.

5.1053-{4-[4-(3,3-DIFLUORO-AZETIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To a 20-mL reaction vial charged with3-(4-((4-(bromomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300 mg, 0.677 mmol) and 3,3-difluoroazetidine hydrochloride (92 mg,0.711 mmol), was added dry MeCN (10 mL) followed by DIEA (0.355 mL, 2.0mmol). The resulting suspension was warmed to 50° C. After −30 min, thetemperature was raised further to 70° C. and the reaction mixture becameclear. Stirring was continued for ˜16 h at 70° C. The reaction mixturewas cooled to room temperature and then concentrated under vacuum. Theresidue was diluted in EtOAc (˜100 mL) and then extracted with 1N NaHCO₃(2×35 mL) and brine. Drying (Na₂SO₄) and concentration on a rotovap gavea glassy solid. Et₂O (˜20 mL) was added to the glass in small portionsand with intermittent sonication until a well-dispersed solid wasformed. The slurry was agitated vigorously and then filtered on a 15-mLmedium fritted funnel. The cake was washed with additional Et₂O (˜50 mL)and then water (˜50 mL). The remaining solid was suction dried and thendried further in a vacuum oven at 60° C. for several hours to give3-{4-[4-(3,3-difluoro-azetidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas an off-white solid (187 mg, 61% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 18/82 CH₃CN/0.1% H₃PO₄, 4.20 min(99.1%); mp: 175-177° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.06 (m, 1H, CHH),2.34-2.49 (m, 1H, CHH), 2.52-2.64 (m, 1H, CHH), 2.81-3.04 (m, 1H, CHH),3.59 (t, J=12.5 Hz, 4H, CH₂CF₂, CH₂CF₂), 3.72 (s, 2H, CH₂), 4.25 (d,J=17.4 Hz, 1H, CHH), 4.42 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2Hz, 1H, CH), 5.23 (s, 2H, CH₂), 7.25-7.39 (m, 4H, Ar), 7.41-7.59 (m, 3H,Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 45.06, 51.56,61.30, 63.55 (t, J=22.0 Hz, CF₂(CH₂)₂), 69.31, 117.29 (t, J=275.1 Hz,CF₂), 1 14.96, 115.22, 127.71, 128.36, 129.78, 129.93, 133.30, 135.49,137.59, 153.45, 167.97, 170.95, 172.80; LCMS: MH=456; Anal Calcd forC₂₄H₂₃F₂N₃O₄+0.65H₂O: C, 61.70; H, 5.24; N, 8.99; Found: C, 61.70; H,5.01; N, 8.77.

5.1063-{4-[4-(3-METHYL-3-PHENOXY-AZETIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₂Cl₂ solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.35 g, 0.790 mmol) was added 3-methyl-3-phenoxyazetidine (0.142 g,0.869 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.336 ml, 1.974mmol). The mixture was stirred at room temperature overnight. Thereaction mixture was added water (10 mL) and CH₂Cl₂ (10 mL) thenextracted. The organic layer was concentrated and purified on silica gelcolumn to give3-{4-[4-(3-methyl-3-phenoxy-azetidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (250 mg, 60%). Melting point: 127-129° C. LC-MSm/e=526. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240nm, gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stayat 95/5 for 5 min: 6.82 min (94%); ¹H NMR (DMSO-d₆) δ 1.58 (s, 3H, CH₃),1.87-2.14 (m, 1H, CHH), 2.36-2.44 (m, OH, CHH), 2.54-2.64 (m, 1H, CHH),2.82-3.01 (m, 1H, CHH), 3.17 (d, J=7.6 Hz, 2H, CH₂), 3.49 (d, J=7.9 Hz,2H, CH₂), 3.64 (s, 2H, CH₂), 4.16-4.50 (m, 2H, CH₂), 5.11 (dd, J=5.1,13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 6.71 (d, J=7.7 Hz, 2H, Ar),6.84-7.00 (m, 1H, Ar), 7.18-7.29 (m, 2H, Ar), 7.29-7.37 (m, 4H, Ar),7.39-7.60 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.57,22.33, 31.16, 45.06, 51.55, 62.12, 65.47, 69.36, 73.05, 114.94, 115.20,116.40, 120.69, 127.67, 128.41, 129.48, 129.78, 129.93, 133.28, 135.21,138.05, 153.46, 154.73, 167.97, 170.95, 172.80; Anal Calcd forC₃₁H₃₁N₃O₅+0.5H₂O: C: 69.65%; H: 6.03%; N: 7.83%; Found: C: 69.52%; H:5.87%; N: 7.80%.

5.1073-{4-[4-(3,3-DIFLUORO-PYRROLIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the stirred mixture of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.8 mmol) and 3,3-difluoropyrrolidine hydrochloride (136 mg,0.8 mmol) in DCM (10 mL) was added DIPEA (0.28 ml, 1.6 mmol). Theresulting mixture was stirred at room temperature for 22 hrs and thereaction mixture was diluted by DCM (30 mL). The mixture was washed withwater (20 mL) and brine (20 mL). Organic layer was dried by MgSO₄ andconcentrated. The residue was purified by ISCO to give3-{4-[4-(3,3-Difluoro-pyrrolidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (256 mg, 69% yield. HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, 20/80, (CH₃CN/0.1% H₃PO₄), 3.59 min (98.6%);mp: 126-128° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.04 (m, 1H, CHH), 2.15-2.34(m, 2H, CH₂), 2.35-2.44 (m, 1H, CHH), 2.60 (br. s., 1H, CHH), 2.69 (t,J=7.0 Hz, 2H, CH₂), 2.76-3.01 (m, 3H, CHH, CH₂), 3.62 (s, 2H, CH₂),4.20-4.32 (m, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.4 Hz, 1H, CHH), 5.11(dd, J=5.1, 13.2 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 7.22-7.37 (m, 4H, Ar),7.39-7.63 (m, 3H, Ar), 10.97 (s, 1H, NH); 13C NMR (DMSO-d₆) δ 22.33,31.16, 34.92, 35.55 (t, J_(C-F)=22.50 Hz), 51.30, 51.56, 58.24, 60.99(t, J_(C-F)=27.57 Hz), 69.35, 114.97, 115.22, 127.69, 128.62, 129.78,129.93, 130.38, 133.30, 135.44, 137.63, 153.46, 167.97, 170.95, 172.80;LCMS MH=470; Anal. Calcd for C₂₅H₂₅F₂N₃O₄+0.2H₂O: C, 63.47; H, 5.41; N,8.88; Found: C, 63.41; H, 5.46; N, 8.78.

5.108 3-{4-[4-(7-FLUORO-3,4-DIHYDRO-1H-ISOINOLIN-2-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.36 g, 0.812 mmol) was added 7-fluoro-1,2,3,4-tetrahydroisoquinolinehydrochloride (0.198 g, 1.056 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.403 ml, 2.436 mmol). The resultingsolution was stirred at room temperature overnight. Solvent wasevaporated, and methylene chloride (100 ml) was added. The mixture waswashed with water (2×50 ml), brine (50 ml), dried and concentrated to afoamy solid, which was purified by silica gel column (MeOH/CH₂Cl₂) togive3-{4-[4-(7-Fluoro-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.205 g, 49% yield); mp, 132-134° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 90/10 in 5 min, isocratic at 90/10 for 5 min (CH₃CN/0.1% H₃PO₄), 4.75min (95.6%). ¹H NMR (DMSO-d₆) δ 1.90-2.08 (m, 1H, CHH), 2.36-2.48 (m,1H, CHH), 2.53-2.63 (m, 1H, CHH), 2.63-2.72 (m, 2H, CH₂), 2.73-2.82 (m,2H, CH₂), 2.83-3.00 (m, 1H, CHH), 3.54 (s, 2H, CH₂), 3.65 (s, 2H, CH₂),4.21-4.49 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.24 (s, 2H,CH₂), 6.84-7.00 (m, 2H, Ar), 7.09-7.17 (m, 1H, Ar), 7.29-7.42 (m, 4H,Ar), 7.43-7.54 (m, 3H, Ar), 10.97 (s, 1H, NH). 13C NMR (DMSO-d₆) 22.36,27.90, 31.20, 45.10, 50.02, 51.59, 55.13, 61.21, 69.44, 112.49, 112.78,113.07, 115.00, 115.24, 127.74, 128.80, 129.82, 129.93 (d, J_(C-F)=18),130.19, 133.32, 135.33, 136.95 (d, J_(C-F)=8), 138.13, 153.51, 160.20(d, J_(C-F)=240), 168.01, 170.96, 172.82.). LC/MS m/e=514. Anal Calcdfor C₃₀H₂₈N₃O₄F (+0.2H₂O): C, 69.67; H, 5.54; N, 8.12; Found: C, 69.34;H, 5.57; N, 7.96.

5.1093-{4-[4-(4,7-DIHYDRO-5H-THIENO[2,3-C]PYRIDIN-6-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.359 g, 0.810 mmol) was added 4,5,6,7-tetrahydrothieno[2,3-c]pyridinehydrochloride (0.171 g, 0.972 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.402 ml, 2.430 mmol). It became aclear solution after DIPEA was added. The mixture was stirred at roomtemperature overnight. Solvent was evaporated and to the residue wasadded methylene chloride (80 ml). The mixture was washed with water(2×60 ml), brine (50 ml), dried and concentrated to an off-white solid,which was purified by silica gel column (MeOH/CH₂Cl₂) to give3-{4-[4-(4,7-Dihydro-5H-thieno[2,3-c]pyridin-6-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.304 g, 74% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 90/10 in 5min, isocratic at 90/10 for 5 min (CH₃CN/0.1% H₃PO₄), 4.61 min (98.1%).¹H NMR (DMSO-d₆) δ 1.89-2.08 (m, 1H, CHH), 2.35-2.48 (m, 1H, CHH),2.53-2.68 (m, 3H, CHH, CH₂), 2.68-2.77 (m, 2H, CH₂), 2.82-3.00 (m, 1H,CHH), 3.59 (s, 2H, CH₂), 3.68 (s, 2H, CH₂), 4.20-4.48 (m, 2H, CH₂), 5.11(dd, J=5.2, 13.3 Hz, 1H, NCH), 5.24 (s, 2H, CH₂), 6.82 (d, J=5.1 Hz, 1H,Ar), 7.28 (d, J=5.1 Hz, 1H, Ar), 7.31-7.42 (m, 4H, Ar), 7.43-7.56 (m,3H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.36, 25.12, 31.20,45.10, 49.59, 51.36, 51.59, 60.50, 69.45, 115.00, 115.24, 122.61,126.99, 127.72, 128.83, 1′29.81, 129.95, 132.46, 133.32, 133.47, 135.35,138.29, 153.53, 168.01, 170.96, 172.82. LC/MS m/e=502. Anal Calcd forC₂₈H₂₇N₃O₄S (+0.5H₂O): C, 65.86; H, 5.53; N, 8.23; Found: C, 65.64; H,5.44; N, 8.04.

5.1103-{4-[4-(6,7-DIHYDRO-4H-THIENO[3,2-C]PYRIDIN-5-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) suspension of4,5,6,7-tetrahydrothieno[3,2-c]pyridine (0.145 g, 1.038 mmol) was added3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.354 g, 0.799 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.264 ml,1.597 mmol). It became a clear solution after DIPEA was added. Themixture was stirred at room temperature for two hours. Solvent wasevaporated, and methylene chloride (80 ml) was added. The mixture waswashed with water (2×50 ml), brine (50 ml), dried and concentrated to anoil, which was purified by silica gel column (MeOH/CH₂Cl₂) to give3-{4-[4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.312 g, 78% yield); mp, 143-145° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 90/10 in 5 min, isocratic at 90/10 for 5 min (CH₃CN/0.1% H₃PO₄), 4.51min (97.0%). ¹H NMR (DMSO-d₆) δ 1.89-2.06 (m, 1H, CHH), 2.35-2.48 (m,1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.68-2.83 (m, 4H, CH₂, CH₂), 2.84-3.00(m, 1H, CHH), 3.42-3.49 (m, 2H, CH₂), 3.68 (s, 2H, CH₂), 4.20-4.48 (m,2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.24 (s, 2H, CH₂), 6.76(d, J=5.1 Hz, 1H, Ar), 7.25 (d, J=5.1 Hz, 1H, Ar), 7.30-7.41 (m, 4H,Ar), 7.43-7.53 (m, 3H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ22.36, 24.99, 31.20, 45.10, 50.18, 51.59, 52.42, 60.91, 69.45, 115.00,115.24, 122.91, 125.42, 127.72, 128.82, 129.82, 129.95, 132.77, 133.32,133.96, 135.30, 138.38, 153.53, 168.01, 170.96, 172.83. LC/MS m/e=502.Anal Calcd for C₂₈H₂₇N₃O₄S (+0.4H₂O): C, 66.10; H, 5.51; N, 8.26; Found:C, 65.92; H, 5.45; N, 8.00.

5.111 3-{1-OXO-4-[4-(3,3,4,4-TETRAFLUORO-PYRROLIDIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₂Cl₂ solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.35 g, 0.790 mmol) was added 3,3,4,4-tetrafluoropyrrolidinehydrochloride (0.142 g, 0.79 mmol), andN-ethyl-N-isopropylpropan-2-amine (336 μl, 1.974 mmol). The mixture washeated to 70° C. for 3 days. The reaction mixture was concentrated andthe resulted solid was taken up in CH₂Cl₂ (20 mL) and extracted withwater (20 mL). Organic layer was concentrated and purified on silica gelcolumn eluted with CH₂Cl₂ and MeOH to give3-{1-Oxo-4-[4-(3,3,4,4-tetrafluoro-pyrrolidin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas white a solid (120 mg, 30%). Melting point: 164-166° C. LC-MSm/e=506. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240nm, gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stayat 95/5 for 5 min: 6.67 min (96%). ¹H NMR (DMSO-d₆) δ 1.86-2.09 (m, 1H,CHH), 2.34-2.44 (m, 1H, CHH), 2.55-2.67 (m, 1H, CHH), 2.81-3.03 (m, 1H,CHH), 3.15 (t, J=13.4 Hz, 4H, CH₂, CH₂), 3.72 (s, 2H, CH₂), 4.19-4.48(m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.24 (s, 2H, CH₂),7.26-7.39 (m, 4H, Ar), 7.43-7.58 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.33, 31.16, 45.06, 51.56, 57.01, 57.47, 57.82, 58.15,69.29, 114.97, 115.25, 119.39, 122.84, 127.80, 128.75, 129.80, 129.95,133.30, 135.88, 136.13, 153.45, 167.97, 170.95, 172.80; Anal Calcd forC₂₅H₂₃F₄N₃O₄+0.4H₂O: C; 58.57%; H: 4.67%; N: 8.20%; Found: C; 58.46%; H:4.35%; N: 8.08%.

5.1123-(4-{4-[2-(4-FLUORO-PHENYL)-2-METHYL-MORPHOLIN-4-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the CH₂Cl₂ solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.35 g, 0.790 mmol) was added 2-(4-fluorophenyl)-2-methylmorpholine(0.170 g, 0.869 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.336 ml,1.974 mmol). The mixture was stirred at room temperature overnight. Themixture was added water and CH₂Cl₂ then extracted. The organic layer wasconcentrated and purified on silica gel column eluted with CH₂Cl₂ andMeOH to give3-(4-{4-[2-(4-fluoro-phenyl)-2-methyl-morpholin-4-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (0.27 g, 61%). Melting point: 118-120° C. LC-MSm/e=558. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240nm, gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stayat 95/5 for 5 min: 6.90 min (94%); ¹H NMR (DMSO-d₆) δ 1.32 (s, 3H, CH₃),1.87-2.09 (m, 1H, CHH), 2.22-2.46 (m, 4H, CHH, CH₂, CHH), 2.57 (d,J=18.5 Hz, 1H, CHH), 2.93 (br. s., 2H, CHH, CHH), 3.35-3.55 (m, J=1.9Hz, 3H, CH₂, CHH), 3.57-3.76 (m, 1H, CHH), 4.16-4.54 (m, 2H, CH₂),5.00-5.19 (m, 1H, NCH), 5.24 (s, 2H, CH₂), 7.12 (td, J=1.5, 8.9 Hz, 2H,Ar), 7.27-7.41 (m, 6H, Ar), 7.41-7.56 (m, 3H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.33, 27.95, 31.16, 45.06, 51.56, 52.70, 60.63,61.07, 61.77, 69.39, 74.52, 114.40, 114.68, 115.00, 115.22, 127.57,127.76, 127.86, 128.98, 129.77, 129.95, 133.30, 135.37, 137.59, 141.20,153.46, 159.21, 162.42, 167.97, 170.93, 172.80. Anal Calcd forC₃₂H₃₂FN₃O₅: C: 68.93%; H: 5.78%; N: 7.54%; Found: C: 67.20%; H: 5.26%;N: 7.17%.

5.1133-{4-[4-(6-FLUORO-3,4-DIHYDRO-1H-ISOINOLIN-2-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₂Cl₂ of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.35 g, 0.790 mmol) was added 6-fluoro-1,2,3,4-tetrahydroisoquinolinehydrochloride (0.163 g, 0.869 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.336 ml, 1.974 mmol). The mixturewas stirred at room temperature overnight. The mixture was added waterand CH2Cl2 and extracted. The organic layer was concentrated to give asolid. The solid was stirred with ether and the suspension was filteredto give3-{4-[4-(6-Fluoro-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas white solid (0.28 g, 69%). Melting point: 123-125° C. LC-MS m/e=514.HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm,gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stay at95/5 for 5 min: 6.6 min (94%). ¹H NMR (DMSO-d₆) δ 1.88-2.06 (m, 1H,CHH), 2.34-2.48 (m, J=13.4 Hz, 1H, CHH), 2.57 (d, J=18.3 Hz, 1H, CHH),2.62-2.71 (m, 2H, CH₂), 2.76-3.00 (m, 3H, CH₂, CHH), 3.51 (s, 2H, CH₂),3.65 (s, 2H, CH₂), 4.11-4.49 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H,NCH), 5.24 (s, 2H, CH₂), 6.93 (d, J=9.3 Hz, 2H, Ar), 6.99-7.12 (m, 1H,Ar), 7.28-7.43 (m, 4H, Ar), 7.43-7.56 (m, 3H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.33, 28.70, 31.16, 45.07, 49.65, 51.55, 54.75,61.33, 69.42, 112.29, 112.57, 114.36, 114.64, 114.97, 115.22, 127.70,128.02, 128.14, 128.78, 129.78, 129.93, 130.78, 133.30, 135.30, 136.51,136.61, 138.17, 153.49, 158.83, 162.04, 167.97, 170.95, 172.80; AnalCalcd for C₃₀H₂₈FN₃O₄+0.5H₂O: C: 68.95%; H: 5.59%; N: 8.04%; Found: C:68.68%; H: 5.31%; N: 7.89%.

5.1143-{1-OXO-4-[4-(3-PHENYL-5,6-DIHYDRO-8H-IMIDAZO[1,2-A]PYRAZIN-7-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

The mixture of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.8 mmol) and 3-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine(157 mg, 0.8 mmol) in DCM (10 mL) was added DIPEA (0.28 mL, 1.6 mmol).The resulting mixture was stirred at room temperature for 23 hrs andthen added by 3-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (94 mg,0.45 mmol) and DIPEA (0.1 mL, 0.6 mmol). The mixture was concentratedand stirred in acetonitrile (7 mL), DCM (2 mL) and DIPEA (0.2 mL) at 60°C. for 16 hrs. The reaction mixture was diluted by DCM (30 mL) andwashed with water (20 mL) and brine (20 mL). The organic layer was driedby MgSO₄ and concentrated. The residue was purified by ISCO to give3-{1-Oxo-4-[4-(3-phenyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a light yellow solid (82 mg, 18% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 27/73, (CH₃CN/0.1% H₃PO₄), 4.89 min(98.3%); mp: 131-133° C. (in house); ¹H NMR (DMSO-d₆) δ 1.92-2.05 (m,1H, CHH), 2.36-2.47 (m, 1H, CHH), 2.54-2.64 (m, 1H, CHH), 2.84 (t, J=5.4Hz, 2H, CH₂), 2.88-2.99 (m, 1H, CHH), 3.64 (s, 2H, CH₂), 3.74 (s, 2H,CH₂), 4.03 (t, J=5.2 Hz, 2H, CH₂), 4.26 (d, J=17.6 Hz, 1H, CHH), 4.43(d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CHH), 5.26 (s,2H, CH₂), 7.02 (s, 1H, Ar), 7.29-7.38 (m, 3H, Ar), 7.39-7.46 (m, 4H,Ar), 7.46-7.54 (m, 5H, Ar), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ21.43, 30.26, 42.58, 44.17, 48.31, 50.64, 59.57, 68.52, 114.13, 114.33,125.24, 126.26, 126.33, 126.87, 127.83, 128.04, 128.83, 128.90, 129.06,130.23, 132.40, 134.69, 136.60, 142.49, 152.59, 167.08, 170.04, 171.90;LCMS MH=562; Anal. Calcd for C₃₃H₃₁N₅O₄+0.8H₂O+0.31 CH₂Cl₂: C, 66.42; H,5.56; N, 11.63; Found: C, 66.10; H, 5.25; N, 11.49.

5.115 3-{1-OXO-4-[4-(4-TRIFLUOROMETHYL-IMIDAZOL-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2, 6-DIONE

To the CH₃CN solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.35 g, 0.790 mmol) was added4-(trifluoromethyl)-1H-imidazole (0.118 g, 0.869 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.336 ml, 1.974 mmol). The mixturewas heated at 70° C. for 2 days. The reaction mixture was then addedCH₂Cl₂ and water and extracted. The organic layer was concentrated andthe resulted oil was purified on silica gel column eluted with CH₂Cl₂and MeOH to give3-{1-Oxo-4-[4-(4-trifluoromethyl-imidazol-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (80 mg, 20%). Melting point 148-150° C. LC-MS m/e=499.HPLC Waters Symmetry C-18,3.9×150 mm, 5 micro, 1 mL/min, 240 nm,gradient 5/95 to 5/95 CH3CN/0.1% H3PO4 in H2O during 5 min and stay at95/5 for 5 min: 8.89 min (96%). 1H NMR (DMSO-d6) δ1.90-2.05 (m, 1H,CHH), 2.33-2.48 (m,J=4.3, 13.0 Hz, 1H,CHH), 2.57 (d,J=17.9 Hz, 1H, CHH),2.80-2.99 (m, 1H, CHH), 4.18-4.47 (m, 2H, CH2), 5.10 (dd, J=5.1, 13.2Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 5.27 (s, 2H, CH2), 7.25-7.41 (m, 4H,Ar), 7.43-7.57 (m, 3H, Ar), 7.91 (d, J=1.1 Hz, 1H, Ar), 8.00 (s, 1H,Ar), 10.96 (s, 1H, NH); , 13C NMR (DMSO-d6) β22.31, 31.16, 45.04, 49.62,51.55,69.10, 114.91, 115.26, 120.53, 127.83, 128.14, 129.78, 129.95,133.30, 136.49, 136.64, 139.07, 153.36, 167.96, 170.93, 172.80. AnalCaled for C₂₅H₂₁F₃N₄O₄+0.5 H20: C; 59.17%; H, 4.37%; N, 11.04%. Found:C; 59.21%; H, 4.11%; N, 10.90%.

5.1163-(4-{3-[4-(4-FLUORO-PHENYL)-PIPERIDIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINL-2-YL)-PIPERIDINE-2.6-DIOINE

To the CH₃CN (10 ml) solution of3-(4-(3-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.31 g, 0.699 mmol) was added 4-(4-fluorophenyl)piperidinehydrochloride (0.181 g, 0.839 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.347 ml, 2.098 mmol) at roomtemperature. The cloudy mixture was stirred at room temperature for onehour. Solvent was evaporated and the resulting residue was purified bysilica gel column (MeOH/CH₂Cl₂) to give3-(4-{3-[4-(4-Fluoro-phenyl)-piperidin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (0.176 g, 47% yield); mp, 139-141° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 90/10 in 5 min, isocratic at 90/10 for 5 min (CH₃CN/0.1% H₃PO₄), 4.95min (95.5%). ¹H NMR (DMSO-d₆) δ 1.49-1.77 (m, 4H, CH₂, CH₂), 1.89-2.09(m, 3H, CH₂, CHH), 2.35-2.47 (m, 1H, CHH), 2.53-2.62 (m, 1H, CHH),2.81-2.99 (m, 3H, CH₂, CHH), 3.51 (s, 2H, CH₂), 4.20-4.49 (m, 2H, CH₂),5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.27 (s, 2H, CH₂), 7.04-7.15 (m, 2H,Ar), 7.21-7.53 (m, 9H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ15.14, 22.36, 31.18, 33.13, 41.01, 45.12, 51.59, 53.50, 62.18, 69.63,114.75, 115.01, 115.20, 115.26, 126.22, 128.00, 128.34, 128.44, 129.76,129.98, 133.31, 136.47, 138.79, 142.35, 153.44, 160.58 (d, J_(C-F)=242Hz), 167.99, 170.95, 172.79. LC/MS m/e=542. Anal Calcd for C₃₂H₃₂N₃O₄F(+0.2H₂O): C, 70.49; H, 5.99; N, 7.71; Found: C, 70.24; H, 6.14; N,7.58.

5.117 2-(2,6-DIOXO-PIPERIDIN-3-YL)-4-[4-(2-TRIFLUOROMETHYL-5,6,8,8A-TETRAHYDRO-1H-[1,2,4]TRIAZOLO[1,5-A]PYRAZIN-7-YLMETHYL)-BENZYLOXY]-ISOINDOLE-1,3-DIONE

Step 1: Preparation of dimethyl3-((4-(hydroxymethyl)benzyl)oxy)phthalate

Dimethyl 3-hydroxyphthalate (10 g, 47.6 mmol) and(4-(chloromethyl)phenyl)methanol (7.82 g, 50.0 mmol) were dissolved indry DMF (60 mL). To the solution was added K₂CO₃ (6.90 g, 50.0 mmol) andthe mixture was stirred at 80° C. for 16 h. The DMF was removed in vacuoand the residue was partitioned between EtOAc (300 mL) and water (100mL). The organic layer was washed with additional water (100 mL) andbrine, dried (Na₂SO₄), and concentrated in vacuo to dimethyl3-((4-(hydroxymethyl)benzyl)oxy)-phthalate as a viscous amber oil (19g): LCMS: MH=331; The crude product was used in the next step withoutfurther purification

Step 2: Preparation of 3-((4-(Hydroxymethyl)benzyl)oxy)phthalic acidDimethyl 3-(4-(hydroxymethyl)benzyloxy)phthalate (19 g actual wt, 15:72g, 47.6 mmol, assuming quantitative yield from previous step) wasdissolved in THF (30 mL). To the solution was added water (30 mL).Aqueous NaOH (10 N, 25 mL, 250 mmol) was added and the mixture wasvigorously stirred at 70° C. for 2.5 h. The mixture was allowed to coolto rt, concentrated in vacuo to a syrup, and then transferred to a flaskcontaining 6 N HCl (45 mL) over ice. Immediately, solid precipitated outand the slurry was diluted with water (−60 mL). The mixture was filteredon a medium fritted funnel with suction. The cake was washed withadditional water (˜60 mL), suction dried, and then placed in a vacuumoven at 60° C. for 4 h to give 3-((4-(hydroxymethyl)benzyl)oxy)phthalicacid as a pale yellow solid (13.9 g, 97% yield from dimethyl3-hydroxyphthalate): ¹H NMR (DMSO-d₆) δ 4.41-4.58 (m, 2H, CH₂), 5.17 (s,3H, CH₂, OH), 7.20-7.64 (m, 7H, Ar), 13.02 (br. s., 2H, 2×COOH); ¹³C NMR(DMSO-d₆) δ 62.63, 69.73, 117.03, 121.56, 126.46, 126.88, 127.13,128.91, 129.57, 134.87, 142.19, 154.50, 166.45, 167.71; LCMS: MH=303, 94area % at 240 nm. The solid was used in the next step without furtherpurification.

Step 3: Preparation of2-(2,6-Dioxopiperidin-3-yl)-4-((4-(hydroxymethyl)benzyl)oxy)isoindoline-1,3-dione

3-Aminopiperidine-2,6-dione hydrochloride (0.915 g, 5.56 mmol) was addedto a solution of 3-(4-(hydroxymethyl)benzyloxy)phthalic acid (1.4 g,4.63 mmol) in dry pyridine (15 mL) and the mixture was heated to 118° C.in an oil bath for 16 h. The dark reaction mixture was allowed to coolto room temperature and was acidified with slow addition of 1 N HCl (˜25mL). The mixture was further diluted with water (˜170 mL) and thensonicated for ˜30 minutes to help break up solid aggregates. Theresulting dark slurry was filtered on a medium pore fritted funnel andthe dark solid was washed with additional water (70 mL). The cake wassuction dried and then placed in vacuum oven at 60° C. for 2.5 h to give1.6 g of a dark blue solid. The solid was dissolved in a mixture of DCM,MeCN, and MeOH (˜100 mL each) and treated with decolorizing charcoal.The mixture was swirled around and then gravity-filtered using filterpaper. The filtrate/wash (dark amber color) was treated once again withdecolorizing charcoal and then filtered on a bed of celite. The clearfiltrate was concentrated in vacuo to dryness to give a solid which wastriturated with water and filtered with suction. The cake was washedwith additional water (˜100 mL), suction dried, and then placed invacuum oven at 60° C. for 4 h to give2-(2,6-dioxopiperidin-3-yl)-4-((4-(hydroxymethyl)benzyl)oxy)isoindoline-1,3-dioneas an off-white solid (1.2 μm, 68% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 5.08 min(99.9%); mp: 250-252; ¹H NMR (DMSO-d₆) δ 1.95-2.07 (m, 1H, CHH),2.41-2.67 (m, 2H, CHH, CHH), 2.78-3.00 (m, 1H, CHH), 4.50 (d, J=5.1 Hz,2H, CH₂OH), 5.09 (dd, J=5.4, 12.7 Hz, 1H, CH), 5.19 (t, J=5.6 Hz, 1H,OH), 5.36 (s, 2H, CH₂O), 7.24-7.40 (m, 2H, Ar), 7.41-7.53 (m, 3H, Ar),7.59 (d, J=8.5 Hz, 1H, Ar), 7.82 (dd, J=7.4, 8.5 Hz, 1H, Ar), 11.11 (s,1H, NH); ¹³C NMR (DMSO-d₆) δ 21.88, 30.83, 48.67, 62.53, 69.91, 115.40,116.52, 120.18, 126.44, 127.09, 133.17, 134.31, 136.86, 142.32, 155.42,165.21, 166.68, 169.81, 172.66. LCMS: M+Na=417; MH is not observed inpositive ionization mode; Anal Calcd for C₂₁H₁₈N₂O₆: C, 63.96; H, 4.60;N, 7.10; Found: C, 63.77; H, 4.52; N, 7.32.

Step 4 Preparation of4-((4-(Bromomethyl)benzyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

A suspension of2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)benzyloxy)isoindoline-1,3-dione(1.05 g, 2.66 mmol) in a mixture of DCM and MeCN (25 mL, 10 mL) wasstirred in an ice bath. To the mixture was added PBr₃ (0.502 mL, 5.32mmol) in one portion. After 5 min, the ice bath was removed and thereaction mixture was stirred at room temperature for ˜20 h. To thereaction mixture was added NaBr (0.822 g, 7.99 mmol) andtetrabutylammonium bromide (0.077 g, 0.240 mmol) and stirring wascontinued for an additional 14 h at room temperature. The reaction wasconcentrated in vacuo to an off-white solid and the solid was reslurriedin water with vigorous agitation and then filtered (medium frittedfunnel). The cake was washed with copious water (˜250 mL, total volumeof filtrate and washes) and then dried in a vacuum oven at 50° C. togive4-((4-(bromomethyl)benzyl)-oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneas a white solid (1.21 g, 99% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 50/50 CH₃CN/0.1% H₃PO₄, 4.85 min (99.5%);¹H NMR (DMSO-d₆) δ 1.94-2.15 (m, 1H, CHH), 2.42-2.70 (m, 2H, CHH, CHH),2.79-2.99 (m, 1H, CHH), 4.72 (s, 2H, CH₂), 5.10 (dd, J=5.4, 12.9 Hz, 1H,CH), 5.38 (s, 2H, CH₂), 7.38-7.54 (m, 5H, Ar), 7.59 (d, J=8.5 Hz, 1H,Ar), 7.83 (dd, J=7.3, 8.4 Hz, 1H, Ar), 11.11 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 21.95, 30.91, 34.12, 48.75, 69.64, 115.57, 116.62, 120.18,127.48, 129.42, 133.26, 136.33, 136.99, 137.72, 155.37, 165.27, 166.73,169.87, 172.72; LCMS: M+Na=479, 481; MH is not observed.

Step 5: Preparation of2-(2,6-dioxo-piperidin-3-yl)-4-[4-(2-trifluoromethyl-5,6,8,8a-tetrahydro-1H-[1,2,4]triazolo[1,5-a]pyrazin-7-ylmethyl)-benzyloxy]-isoindole-1,3-dione

To the CH₂Cl₂ solution of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(0.13 g, 0.284 mmol) was added2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine(0.060 g, 0.313 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.152 ml,0.853 mmol). The mixture was stirred at room temperature overnight. Tothe reaction mixture was added water (10 mL) and CH₂Cl₂ (10 mL) andextracted. The organic layer was concentrated and the resulted oil waspurified on silica gel column eluted with MeOH and CH₂Cl₂ to give2-(2,6-dioxo-piperidin-3-yl)-4-[4-(2-trifluoromethyl-5,6,8,8α-tetrahydro-1H-[1,2,4]triazolo[1,5-a]pyrazin-7-ylmethyl)-benzyloxy]-isoindole-1,3-dioneas a white solid (120 mg, 74%). Melting point: 128-130° C. LC-MSm/e=569. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240nm, isocratic 50/50 CH₃CN/0.1% H₃PO₄ in H₂O: t_(R)=3.64 min (99%); ¹HNMR (DMSO-d₆) δ 1.94-2.12 (m, 1H, CHH), 2.41-2.47 (m, 1H, CHH),2.54-2.67 (m, 1H, CHH), 2.77-2.95 (m, 1H, CHH), 3.01 (t, J=5.4 Hz, 2H,CH₂), 3.81 (d, J=7.6 Hz, 4H, CH₂, CH₂), 4.24 (t, J=5.1 Hz, 2H, CH₂),5.09 (dd, J=5.4, 12.7 Hz, 1H, NCH), 5.37 (s, 2H, CH₂), 7.37-7.55 (m, 5H,Ar), 7.61 (d, J=8.5 Hz, 1H, Ar), 7.76-7.88 (m, 1H, Ar), 11.11 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 21.95, 30.90, 46.54, 47.67, 48.73, 49.21,59.42, 69.89, 115.53, 116.59, 120.21, 127.42, 128.95, 133.26, 135.25,136.99, 137.06, 152.84, 155.50, 165.29, 166.75, 169.87, 172.71. AnalCalcd for C₂₇H₂₃F₃N₆O₅+0.5H₂O+0.2 Et₂O: C: 56.37%; H: 4.42%; N: 14.19%.Found C: 56.27%; H: 4.20%; N: 14.05%.

5.118 3-(4-((4-(((3R,5S)-3,5-DIMETHYLMORPHOLINO)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE HYDROCHLORIDE

Step 1: To a slurry of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(250 mg, 0.526 mmol) in acetonitrile (5 mL) was added(3R,5S)-3,5-dimethylmorpholine (79 mg, 0.684 mmol) as a solid. Themixture was stirred with intermittent sonication to give a clearsolution and then DIEA (0.197 mL, 1.128 mmol) was added. The resultingclear solution was stirred at room temperature. After about 24 h, more(3R,5S)-3,5-dimethylmorpholine (79 mg, 0.526 mmol) was added and themixture was allowed to stir for an additional 24 h at room temperature.The reaction mixture was concentrated in vacuo to give (S)-methyl5-amino-4-(4-((4-(((3R,5S)-3,5-dimethylmorpholino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas an oily residue (268 mg). The crude product was used in the next stepwithout further purification, LCMS: MH=510.

Step 2: The oil obtained in step 1, methyl5-amino-4-(4-(4-(((3R,5S)-3,5-dimethylmorpholino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(268 mg, 0.526 mmol, assuming quantitative yield from previous step) wasdissolved in DMF (5 mL). To the solution was added anhydrous potassiumcarbonate (189 mg, 1.367 mmol) and the mixture was stirred at 85° C. forabout 6 h. Heating was discontinued over weekend (sample stored at 4°C.) and then resumed again for an additional 24 h. The cooled reactionmixture was diluted with EtOAc (˜100 mL) and then washed with 1N aq.NaHCO₃ (30 mL) and brine. The organic layer was dried over Na₂SO₄ andthen concentrated in vacuo to give a tan oil. The oil was dissolved inDMF (8 mL) and purified using reversed-phase preparative HPLC. Theproduct was eluted with an acetonitrile/water gradient (0.1% formic acidin both mobile phases, 5 to 50% MeCN over 20 minutes) and fractions werecollected by mass trigger. The desired fractions were combined, treatedwith 1 N HCl (3 mL), and then concentrated in vacuo to give a glassysolid. The solid was treated with 2 N HCl in Et₂O (1 mL) andconcentrated in vacuo. The resulting solid was placed in vacuum oven at60° C. for several hours to give3-(4-((4-(((3R,5S)-3,5-dimethylmorpholino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride as a white solid (130 mg, 48% yield): HPLC: WatersSymmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 5% grad 95% in 10 min,CH₃CN/0.1% H₃PO₄, 5.90 min (96.2%); mp: 235-237° C.; ¹H NMR (DMSO-d₆with D₂O) δ 0.89 (d, J=6.2 Hz, 6H, CH₃, CH₃), 1.96-2.15 (m, 1H, CHH),2.41-2.53 (m, 3H, CHH, CH, CH), 2.58-2.70 (m, 1H, CHH), 2.80-2.98 (m,1H, CHH), 3.00-3.19 (m, 2H, morph. CHH, CHH), 3.65 (dd, J=2.9, 11.2 Hz,2H, morph. CHH, CHH), 3.78 (br. s., 2H, CH₂), 4.31 (d, J=17.6 Hz, 1H,CHH), 4.45 (d, J=17.6 Hz, 1H, CHH), 5.09 (dd, J=5.1, 13.2 Hz, 1H, CH),5.23 (s, 2H, CH₂), 7.29-7.58 (m, 7H, Ar); ¹³C NMR (DMSO-d₆) δ 17.73,24.16, 32.97, 47.23, 50.90, 53.61, 55.17, 56.71, 71.34, 74.46, 117.03,117.20, 129.39, 129.90, 131.81, 131.90, 134.99, 136.37, 142.45, 155.36,170.27, 172.80, 174.91; LCMS: MH=478; Anal Calcd for C₂₇H₃₁N₃O₅.+0.95HCl: C, 63.31; H, 6.29; N, 8.20; Found: C, 63.51; H, 6.20; N, 7.91.

5.1193-(1-OXO-4-((3-((2-(TRIFLUOROMETHYL)-5,6-DIHYDRO-[1,2,4]TRIAZOLO[1,5-A]PYRAZIN-7(8H)-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To the stirred solution of3-(4-(3-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(500 mg, 1.13 mmol) in DCM (10 mL) was added2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine(238 mg, 1.24 mmol) and DIPEA (0.59 mL, 3.38 mmol). The resultingsolution was stirred at 40° C. for 27 hrs. The reaction mixture wasadded by DCM (30 mL) and brine (20 mL). The mixture was extracted andorganic layer was dried by MgSO₄ and concentrated. The residue waspurified by give a glass like solid. The solid was stirred in EtOAc (5mL) and stirred in diethyl ether (40 mL) to give3-(1-oxo-4-((3-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (391 mg, 62% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50, (CH₃CN/0.1% H₃PO₄), 3.25 min(95.7%); mp: 213-215° C.; ¹H NMR (DMSO-d₆) δ 1.92-2.06 (m, 1H, CHH),2.34-2.47 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.82-3.07 (m, 3H, CHH,CH₂), 3.81 (s, 4H, CH₂, CH₂), 4.17-4.49 (m, 4H, CHH, CHH, CH₂),5.05-5.16 (m, 1H, CHH), 5.27 (s, 2H, CH₂), 7.28-7.54 (m, 7H, Ar), 10.97(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 45.09, 46.52, 47.73,49.14, 51.58, 59.55, 69.55, 115.13, 115.28, 126.72, 128.06, 128.44,128.59, 129.77, 129.96, 133.30, 136.81, 137.47, 152.82, 153.45, 167.96,170.95, 172.78; LCMS MH=555; Anal. Calcd for C₂₇H₂₅F₃N₆O₄: C, 58.48; H,4.54; N, 15.16; Found: C, 58.53; H, 4.21; N, 14.89.

5.1203-{1-OXO-4-[3-(4-TRIFLUOROMETHANESULFONYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the stirred solution of3-(4-(3-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(500 mg, 1.13 mmol) in DCM (10 ml) was added by1-(trifluoromethylsulfonyl)piperazine (320 mg, 1.47 mmol) and DIPEA(0.59 ml, 3.38 mmol). The resulting solution was stirred at 40° C. for22 hrs. The reaction mixture was added by DCM (30 mL) and brine (20 mL).The mixture was extracted and organic layer was dried by MgSO₄ andconcentrated. The residue was purified by ISCO give a glass like solid.The solid was stirred in EtOAc (5 mL) and diethyl ether (40 mL) to give3-{1-Oxo-4-[3-(4-trifluoromethanesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (257 mg, 39% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 27/73, (CH₃CN/0.1% H₃PO₄), 4.82 min(99.9%); mp: 150-152° C.; ¹H NMR (DMSO-d₆) δ 1.92-2.05 (m, 1H, CHH),2.35-2.48 (m, 5H, CH₂, CH₂, CHH), 2.52-2.64 (m, 1H, CHH), 2.83-3.00 (m,1H, CHH), 3.41-3.53 (m, 4H, CH₂, CH₂), 3.57 (s, 2H, CH₂), 4.26 (d,J=17.4 Hz, 1H, CHH), 4.42 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.3Hz, 1H, CHH), 5.25 (s, 2H, CH₂), 7.25-7.35 (m, 3H, Ar), 7.35-7.43 (m,3H, Ar), 7.44-7.53 (m, 1H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.33, 31.16, 45.06, 46.36, 51.56, 51.81, 61.11, 69.54, 115.13, 115.26,126.49, 128.04, 128.46, 129.77, 129.95, 133.30, 136.64, 137.67, 153.43,167.96, 170.93, 172.78; LCMS MH=581; Anal. Calcd for C₂₆H₂₇F₃N₄O₆S+0.1EtOAC+0.1 Et₂O: C, 53.94; H, 4.86; N, 9.39; Found: C, 54.05; H, 4.77; N,9.16.

5.121 3-(1-OXO-4-{3-[4-(2,2,2-TRI FLUORO-ETHYL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(3-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.495 g, 1.117 mmol) (in fact 0.55 g but deducted 10% wt THF) was added1-(2,2,2-trifluoroethyl)piperazine dihydrochloride (0.323 g, 1.340 mmol)and N-ethyl-N-isopropylpropan-2-amine (0.738 ml, 4.47 mmol) at roomtemperature. The cloudy mixture became clear as soon as DIPEA added. Thesolution was stirred for 15 minutes and evaporated under vacuum to getrid of CH₃CN. The resulting residue was purified by silica gel column(MeOH/CH₂Cl₂) to give3-(1-Oxo-4-{3-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-ylmethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (0.485 g, 82% yield); mp, 112-114° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 20/80for 10 minutes, (CH₃CN/0.1% H₃PO₄), 5.64 min (99.9%). ¹H NMR (DMSO-d₆) δ1.92-2.06 (m, 1H, CHH), 2.28-2.48 (m, 5H, CHH, CH₂, CH₂), 2.53-2.66 (m,5H, CHH, CH₂, CH₂), 2.83-3.00 (m, 1H, CHH), 3.12 (q, J=10.3 Hz, 2H,CH₂), 3.47 (s, 2H, CH₂), 4.21-4.48 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2Hz, 1H, NCH), 5.25 (s, 2H, CH₂), 7.20-7.28 (m, 1H, Ar), 7.28-7.41 (m,5H, Ar), 7.44-7.52 (m, 1H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ22.38, 31.20, 45.10, 51.59, 52.42, 53.09, 56.27, 56.65, 57.04, 57.42,61.67, 69.58, 115.17, 115.26, 124.09, 126.27, 127.81, 127.93, 128.35,129.78, 129.97, 133.32, 136.53, 138.37, 153.44, 167.99, 170.95, 172.80.LCMS: m/e=531. Anal Calcd for C₂₇H₂₉N₄O₄F₃(+0.1H₂O, +0.1 EtOAc): C,60.81; H, 5.59; N, 10.35; Found: C, 60.72; H, 5.65; N, 10.09.

5.1223-{4-[3-(3,4-DIHYDRO-1H-ISOQUINOLIN-2-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(3-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.222 g, 0.501 mmol) was added 1,2,3,4-tetrahydroisoquinolinehydrochloride (0.102 g, 0.601 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.207 ml, 1.253 mmol) at roomtemperature. The cloudy mixture was stirred at room temperature for 40minutes and was evaporated under vacuum to get rid of CH₃CN. Theresulting residue was purified by silica gel column (MeOH/CH₂Cl₂) togive3-{4-[3-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas an off-white solid (0.198 g, 80% yield); mp, 117-119° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 20/80for 10 minutes, (CH₃CN/0.1% H₃PO₄), 6.88 min (99.9%). ¹H NMR (DMSO-d₆) δ1.90-1.99 (m, 1H, CHH), 2.32-2.47 (m, 1H, CHH), 2.53-2.62 (m, 1H, CHH),2.63-2.71 (m, 2H, CH₂), 2.75-2.83 (m, 2H, CH₂), 2.84-2.98 (m, 1H, CHH),3.53 (s, 2H, CH₂), 3.67 (s, 2H, CH₂), 4.20-4.45 (m, 2H, CH₂), 5.10 (dd,J=5.1, 13.2 Hz, 1H, NCH), 5.26 (s, 2H, CH₂), 6.94-7.15 (m, 4H, Ar),7.28-7.53 (m, 7H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 14.07,22.35, 28.64, 31.21, 45.09, 50.15, 51.59, 55.38, 61.58, 69.63, 115.14,115.26, 125.43, 125.93, 126.29, 126.35, 127.88, 128.34, 128.42, 129.79,129.95, 133.32, 134.05, 134.74, 136.62, 138.70, 153.47, 167.99, 170.95,172.80. LC/MS m/e=496. Anal Calcd for C₃₀H₂₉N₃O₄ (+0.3H₂O, +0.3 EtOAc):C, 71.05; H, 6.12; N, 7.97; Found: C, 71.00; H, 6.14; N, 7.91.

5.123 3-(4-((3-((4-(4-CHLOROPHENYL)PIPERIDIN-1-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To the CH₂Cl₂ solution of3-(4-(3-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.5 g, 1.128 mmol) was added 4-(4-chlorophenyl)piperidine (0.232 g,1.184 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.602 ml, 3.38 mmol).The solution was stirred at room temperature overnight. The mixture wasadded water (10 mL), CH₂Cl₂ (15 mL) and extracted. The organic layer wasconcentrated then purified on silica gel column eluted with CH₂Cl₂ andMeOH to give3-(4-((3-((4-(4-chlorophenyl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas white solid (340 mg, 54%). Melting point: 180-182° C. LC-MS m/e=558,560. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm,isocratic 30/70 CH₃CN/0.1% H₃PO₄ in H₂O: 4.34 min (99%). ¹H NMR(DMSO-d₆) δ 1.49-1.78 (m, 4H, CH₂, CH₂), 1.89-2.10 (m, 3H, CHH, CH₂),2.33-2.47 (m, 2H, CHH, CH), 2.53-2.61 (m, J=13.8 Hz, 1H, CHH), 2.79-2.98(m, J=11.5 Hz, 3H, CH₂, CHH), 3.51 (s, 2H, CH₂), 4.20-4.50 (m, 2H, CH₂),5.11 (dd, J=5.0, 13.1 Hz, 1H, NCH), 5.27 (s, 2H, CH₂), 7.19-7.53 (m,11H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.34, 31.16, 32.85,41.09, 45.09, 51.55, 53.40, 62.13, 69.58, 115.16, 115.23, 126.20,127.95, 128.17, 128.30, 128.40, 128.56, 129.74, 129.96, 130.41, 133.30,136.46, 138.75, 145.17, 153.42, 167.97, 170.93, 172.78. Anal Calcd forC₃₂H₃₂ClN₃O₄: C %: 68.87; H %: 5.78; N %: 7.53; Found: C %: 68.59; H %:5.83; N %: 7.39.

5.124 4-((4-((3,4-DIHYDROISOINOLIN-2(1H)-YL)METHYL)BENZYL)OXY)-2-(2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE

To the CH₂Cl₂ suspension of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(0.25 g, 0.547 mmol) was added 1,2,3,4-tetrahydroisoquinoline (0.080 g,0.601 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.212 g, 1.640 mmol).The mixture was stirred at room temperature overnight. The mixture wasadded CH2Cl2 and water and extracted. The organic layer was concentratedand purified on silica gel column eluted with CH₂Cl₂ and MeOH to give asolid. The solid was recrystallized from CH₃CN (3 mL) to give4-((4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneas a yellow solid (90 mg, 32%). Melting point (determined in house):124-126° C. LC-MS m/e=510. HPLC Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, isocratic 30/70 CH₃CN/0.1% H₃PO₄ in H₂O: 3.52min (98.5%). ¹H NMR (DMSO-d₆) δ 1.97-2.11 (m, 1H, CHH), 2.42-2.47 (m,1H, CHH), 2.54-2.62 (m, 3H, CHH, CH₂), 2.64-2.71 (m, 2H, CH₂), 2.76-2.98(m, 3H, CHH, CH₂), 3.54 (s, 2H, CH₂), 3.66 (s, 2H, CH₂), 5.03-5.16 (m,1H, NCH), 5.37 (s, 2H, CH₂), 6.94-7.12 (m, 3H, Ar), 7.37-7.44 (m, 2H,Ar), 7.45-7.53 (m, 3H, Ar), 7.61 (d, J=8.3 Hz, 1H, Ar), 7.83 (dd, J=7.5,8.4 Hz, 1H, Ar), 11.11 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 21.09, 27.77,30.06, 47.89, 49.30, 54.57, 60.62, 69.13, 114.65, 119.38, 124.57,125.06, 125.46, 126.48, 127.54, 127.95, 132.41, 133.21, 133.87, 133.94,136.13, 137.43, 154.69, 164.45, 165.90, 169.02, 171.87. Anal Calcd forC₃₀H₂₇N₃O₅C: 70.71%; H: 5.34%; N: 8.25%; Found: C: 67.07%; H: 5.12%; N:7.81%.

5.125 3-(4-((3-((4-(2,4-DIFLUOROPHENYL)PIPERIDIN-1-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To the CH₂Cl₂ solution of3-(4-(3-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.45 g, 1.015 mmol) was added 4-(2,4-difluorophenyl)piperidine (0.210g, 1.066 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.542 ml, 3.05mmol). The mixture was stirred at room temperature overnight. Themixture was added water and CH₂Cl₂, extracted and purified on silica gelcolumn eluted with MeOH and CH₂Cl₂ to give3-(4-((3-((4-(2,4-difluorophenyl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (250 mg, 44%). Melting point: 211-213° C. LC-MSm/e=560. HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm,isocratic 30/70 CH₃CN/0.1% H₃PO₄: 4.68 min (97.6%). ¹H NMR (DMSO-d₆) δ1.66 (br. s., 4H, CH₂, CH₂), 1.89-2.07 (m, 3H, CH₂, CHH), 2.43 (dd,J=4.3, 13.0 Hz, 1H, CHH), 2.53-2.61 (m, J=19.3 Hz, 1H, CHH), 2.73 (quin,J=7.5 Hz, 1H, CH), 2.82-3.03 (m, 3H, CH₂, CHH), 3.51 (s, 2H, CH₂),4.11-4.52 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.27 (s, 2H,CH₂), 7.02 (td, J=2.2, 8.5 Hz, 1H, Ar), 7.10-7.21 (m, 1H, Ar), 7.24-7.54(m, 8H, Ar), 10.97 (s, 1H, NH). 3C NMR (DMSO-d₆) δ 22.34, 31.16, 31.61,34.62, 51.58, 53.43, 62.12, 69.60, 103.20, 103.54, 103.90, 111.21,111.49, 115.16, 115.25, 126.21, 127.96, 128.31, 128.41, 128.62, 128.68,128.87, 128.98, 129.07, 129.74, 129.96, 133.30, 136.48, 138.74, 153.43,158.17, 158.33, 158.84, 159.02, 161.42, 161.58, 162.08, 162.26, 167.97,170.93, 172.77. Anal Calcd for C₃₂H₃₁F₂N₃O₄: C %: 68.68; H %: 5.58; N %:7.51; Found: C %: 68.57; H %: 5.52; N %: 7.60.

5.1263-{1-OXO-4-[4-(2-TRIFLUOROMETHYL-5,6-DIHYDRO-8H-[1,2,4]TRIAZOLO[1,5-A]PYRAZIN-7-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the stirred mixture of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(1.0 g, 2.256 mmol) and2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine(0.477 g, 2.481 mmol) in MeCN (15 mL) was added DIPEA (1.0 mL, 5.6mmol). The resulting mixture was heated at 50° C. for 16 hrs andconcentrated to around 3 mL followed by the addition of Et₂O (40 mL).The mixture was stirred at room temperature and solid was formed. Thesolid was purified by being stirred in CH₃CN (17 mL) at reflux to give3-{1-Oxo-4-[4-(2-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[1,5-a]pyrazin-7-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (580 mg, 46% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60, (CH₃CN/0.1% H₃PO₄), 6.32 min(99.8%); mp: 215-217° C.; ¹H NMR (DMSO-d₆) δ 1.92-2.05 (m, 1H, CHH),2.35-2.48 (m, 1H, CHH), 2.53-2.63 (m, 1H, CHH), 2.83-2.98 (m, 1H, CHH),3.02 (t, J=5.4 Hz, 2H, CH₂), 3.81 (d, J=5.3 Hz, 4H, CH₂, CH₂), 4.19-4.32(m, 3H, CHH, CH₂), 4.42 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2Hz, 1H, CHH), 5.25 (s, 2H, CH₂), 7.29-7.37 (m, 2H, Ar), 7.37-7.44 (m,2H, Ar), 7.45-7.53 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.29, 31.11, 45.02, 46.49, 47.67, 49.12, 51.52, 59.38, 69.29, 114.93,115.19, 127.75, 128.87, 129.75, 129.89, 133.26, 135.69, 136.99, 152.77,153.42, 167.92, 170.89, 172.74; LCMS MH=555; Anal. Calcd forC₂₇H₂₅F₃N₆O₄: C, 58.48; H, 4.54; N, 15.16; Found: C, 58.50; H, 4.23; N,15.08; Chiral HPLC: Chiral AGP/C₁₈, 4.0×150 mm, 5 μm, 0.8 mL/min, UV 240nm, mobile phase A: MeOH, mobile phase B: NH4OAc 10 mM), 20/80, at 8.78min (1.37%) and 11.51 min (93.56%); ee%=(93.56-1.37)/(93.56+1.37)*100%=97%.

5.1272-(2,6-DIOXO-PIPERIDIN-3-YL)-4-(4-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-ISOINDOLE-1,3-DIONE

Step 1: To a solution of dimethyl 3-hydroxyphthalate (1.0 g, 4.76 mmol)in THF (40 ml, 488 mmol), was added triphenyl phosphine on polystyreneresin (1.6 μm/mmol, 4.76 g, 7.61 mmol). After allowing the resin toswell for several minutes at room temperature, the reaction mixture wascooled in an ice bath at 0° C. To the stirred mixture, DIAD (1.48 mL,7.61 mmol) was added dropwise. After about 10 minutes,(4-(morpholinomethyl)phenyl)methanol (1.48 g, 7.14 mmol) was added inone portion. The resulting mixture was stirred at room temperature for20 min. The resin was removed by filtration and rinsed on a frittedfunnel with suction using alternating MeOH and DCM washes twice. Thecombined filtrate was concentrated in vacuo to give the crude product asa yellow oil (4 g). The oil was partitioned between EtOAc (200 mL) and0.25N HCl (150 mL). The organic layer was washed with an additional 100mL of 0.25N HCl. The aqueous layer, containing the product, wasconcentrated on a rotovap to a syrup (about 10 mL). The syrup waspartitioned between EtOAc (300 mL) and 1 N NaOH (100 mL). The aqueouslayer was washed with another portion of EtOAc (about 200 mL). Thecombined organic layers was washed with brine, dried (Na₂SO₄),concentrated in vacuo, and dried in a vacuum oven at 40° C. overnight togive 3-(4-morpholin-4-ylmethyl-benzyloxy)-phthalic acid dimethyl esteras a pale yellow oil (2.6 g). The crude product was used in the nextstep without further purification.

Step 2: To a solution of dimethyl3-(4-(morpholinomethyl)benzyloxy)phthalate (1.9 g, 4.76 mmol) in THF (20ml, 244 mmol), was added water (0.180 ml, 9.99 mmol). With stirring atrt, KO′Bu (9.99 ml, 9.99 mmol, 1M in THF) was added dropwise. Afterabout 24 h, water (1 mL) was added and the mixture was warmed up to 45°C. After about 22 h, the mixture was diluted with Et₂O (100 mL) andfiltered through a fritted funnel. The solid was acidified with aqueous1 N HCl (10 mL) and the resulting mixture was concentrated to dryness onrotovap to give a white solid (2.2 g) that was determined by LCMS to bea ˜1:3 mixture of 3-(4-morpholin-4-ylmethyl-benzyloxy)-phthalic acid1-methyl ester and 3-(4-morpholin-4-ylmethyl-benzyloxy)-phthalic acid,respectively. The mixture was used in the next step without furtherpurification.

Step 3: To a suspension of 3-(4-morpholin-4-ylmethyl-benzyloxy)-phthalicacid 1-methyl ester and 3-(4-morpholin-4-ylmethyl-benzyloxy)-phthalicacid (1.7 g, 3.75 mmol, assuming 82 wt %) in pyridine (30 mL), was addedrac. 3-aminopiperidine-2,6-dione hydrochloride (0.803 g, 4.88 mmol) as asolid. A reflux condenser was placed on RBF and the resulting mixturewas heated in an oil bath at 118° C. for about 24 h. The reactionmixture was allowed to cool down to rt and then concentrated in vacuo toremove most of the pyridine. The remaining dark solid residue wasslurried in EtOAc (about 100 mL), stirred overnight at room temperature,then filtered on a medium fritted funnel. The solid was washed withcopious EtOAc and then suction dried. The remaining solid wastransferred to a flask with EtOAc (400 mL) and 0.5N aq NaHCO₃ (100 mL).The mixture was vigorously stirred for overnight. The phases wereseparated and the aqueous layer was extracted with additional EtOAc(˜300 mL). The combined organic layers was washed with brine and thentreated with Na₂SO₄ and decolorizing charcoal. The slurry was mixed andthen filtered on a bed of Supercell. The clear filtrate was concentratedin vacuo and the resulting white foam was dissolved in minimal MeCN (˜3mL). To the solution was added Et₂O in small portions (about 25 mL,total), resulting in a white precipitate. The slurry was sonicated tobreak up all solid aggregates into a well-dispersed suspension. Theslurry was then filtered and the cake was washed with several smallportions of Et₂O (˜50 mL, total). The cake was suction dried and thenfurther dried in a vacuum oven at 55° C. to give2-(2,6-dioxo-piperidin-3-yl)-4-(4-morpholin-4-ylmethyl-benzyloxy)-isoindole-1,3-dioneas a white solid (950 mg, 55% yield over Step 1-3): HPLC: WatersSymmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 17/83 CH₃CN/0.1%H₃PO₄, 5.34 min (99.8%); mp: 205-207° C.; 1H NMR (DMSO-d₆) δ 1.92-2.14(m, 1H, CHH), 2.28-2.42 (m, 4H, CH₂, CH₂), 2.43-2.66 (m, 2H, CHH, CHH),2.78-3.00 (m, 1H, CHH), 3.46 (s, 2H, CH₂), 3.52-3.64 (m, 4H, CH₂, CH₂),5.09 (dd, J=5.4, 12.9 Hz, 1H, CH), 5.35 (s, 2H, CH₂), 7.29-7.39 (m, 2H,Ar), 7.42-7.52 (m, 3H, Ar), 7.60 (d, J=8.5 Hz, 1H, Ar), 7.82 (dd, J=7.4,8.5 Hz, 1H, Ar), 11.11 (s, 1H, NH); C NMR (DMSO-d₆) δ 21.88, 30.84,48.67, 53.06, 62.01, 66.08, 69.85, 115.42, 116.50, 120.11, 127.18,128.93, 133.18, 134.72, 136.91, 137.61, 155.44, 165.21, 166.68, 169.80,172.66; LCMS: MH=464; Anal Calcd for C₂₅H₂₅N₃O₆+0.06H₂O: C, 64.64; H,5.45; N, 9.04; H₂O, 0.23; Found: C, 64.75; H, 5.13; N, 8.91; H₂O, 0.23.

5.1283-[1-OXO-4-(4-PHENOXYMETHYL-BENZYLOXY)-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Preparation of methyl5-amino-5-oxo-4-(1-oxo-4-(4-(phenoxymethyl)benzyloxy)isoindolin-2-yl)pentanoate

To the acetonitrile solution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.5 g, 1.711mmol) was added 1-(bromomethyl)-4-(phenoxymethyl)benzene (0.474 g, 1.711mmol) and potassium carbonate (0.236 g, 1.711 mmol). The mixture wasstirred at 50° C. for 3 days. The mixture was cooled down to roomtemperature, concentrated and purified on silica gel column eluted withCH₂Cl₂ and MeOH to give methyl5-amino-5-oxo-4-(1-oxo-4-(4-(phenoxymethyl)benzyloxy)isoindolin-2-yl)pentanoateas white solid (0.8 g, 47%).

Step 2: Preparation of3-[1-Oxo-4-(4-phenoxymethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione

To the THF solution of methyl5-amino-5-oxo-4-(-oxo-4-(4-(phenoxymethyl)benzyloxy)isoindolin-2-yl)pentanoate (0.8 g, 1.638 mmol) was added potassiumtert-butoxide (0.202 g, 1.801 mmol) at −78° C. The mixture was stirredat this temperature for 1 hr then was added water and CH₂Cl₂. Afterextraction, the organic layer was concentrated to give3-[1-Oxo-4-(4-phenoxymethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas white solid (0.70 g, 94%). Melting point determined in house:110-112° C. LC-MS m/e=457. HPLC Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂Oduring 5 min and stay at 95/5 for 5 min: 10.48 min (96%). ¹H NMR(DMSO-d₆) δ 1.90-2.04 (m, 1H, CHH), 2.31-2.48 (m, J=4.3, 13.2 Hz, 1H,CHH), 2.52-2.65 (m, 1H, CHH), 2.80-3.01 (m, 1H, CHH), 4.16-4.50 (m, 2H,CH₂), 5.03-5.16 (m, 3H, NCH, CH₂), 5.26 (s, 2H, CH₂), 6.88-7.05 (m, 3H,Ar), 7.21-7.37 (m, 4H, Ar), 7.42-7.56 (m, 5H, Ar), 10.97 (s, 1H, NH);CNMR (DMSO-d6): δ 15.11, 22.33, 31.17, 45.077, 51.57, 68.72, 69.28,114.73, 114.97, 115.25, 120.68, 127.76, 129.45, 129.79, 129.96, 133.31,136.16, 136.94, 153.41, 158.22, 167.98, 170.94, 170.94, 172.80. AnalCalcd for C₂₇H₂₄N₂O₅+0.3H₂O, C, 71.04%, H, 5.30%, N, 6.14%; Found: C,69.89%, H, 5.48%, N, 5.82%.

5.129 tert-BUTYL5-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YLOXY)METHYL)ISOINDOLINE-2-CARBOXYLATE

Step 1: Sodium hydride (60%, 3.6 g, 90.5 mmol) was added to a stirredsolution of N-BOC-propargylamine (10.8 g, 69.6 mmol) in THF (80 mL). Theresulting suspension was stirred at room temperature for 30 minutes anda solution of propargyl bromide/toluene (80%, 16.6 g, 111.3 mmol) wasadded dropwise (slight exothermic!). The mixture was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated and theresidue was dissolved in EtOAc (150 mL) and washed with water (4×40 mL)amd brine (40 mL), and dried. The solvent was removed and the residuewas purified by chromatography (SiO₂, EtOAc: Hexane 30: 70 to 80: 20) togive N-BOC-diprop-2-ynyl-amine (8.5 g, 63% yield): ¹H NMR (CDCl₃) 51.48(s, 9H), 2.22 (s, 2H), 4.17 (b, 4H).

Step 2: Propargyl alcohol (7.3 g, 144.9 mmol) was added dropwise to astirred solution of N-BOC-diprop-2-ynyl-amine (7.0 g, 36.2 mmol) inabsolute ethanol (150 mL) at 3° C. Tris(triphenylphosphine)rhodiumdichloride (1.0 g) was added in one portion. The resulting mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated and the residue was purified by chromatography (SiO₂,EtOAc: Hexane 10: 90 to 40: 60) to give5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester(5.2 g, 57% yield): ¹H NMR (CDCl₃) δ 1.51 (s, 9H), 2.07 (b, 1H), 4.62(s, 4H), 4.68 (d, J=5.7 Hz, 2H), 7.20-7.27 (m, 3H).

Step 3: Diisopropyl azodicarboxylate (1.0 g, 5.0 mmol) was added to astirred suspension of triphenylphosphine-polymer bound (4.3 g, 5.3 mmol)in THF (40 mL) at 3-5° C. The mixture was stirred at 3° C. for 10minutes and a solution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0 g, 3.3mmol) and 5-hydroxmethyl-1,3-dihydro-isoindole-2-carboxylic acidtert-butyl ester (1.1 g, 4.3 mmol) in THF (60 mL) at 3-6° C. Afterstirred at 3° C. for 5 minutes, the mixture was stirred at roomtemperature overnight. The reaction mixture was filtered and solid waswashed with CH₂Cl₂ (30 mL). Filtrate was concentrated and the residuewas dissolved in CH₂Cl₂ (80 mL) and washed with sat. NaHCO₃ (25 mL),water (2×25 mL), and brine (25 mL), and dried. The solvent was removedand the residue was purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3:97) to give tert-butyl5-((2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)isoindoline-2-carboxylate(1.3 g, 73% yield): ¹H NMR (CDCl₃) δ 1.52 (s, 9H), 2.17-2.41 (m, 4H),3.64 (s, 3H), 4.36-4.46 (dd, J=17.7 and 29.4 Hz, 2H), 4.67-4.71 (m, 4H),4.91 (m, 1H), 5.15 (s, 2H), 5.43 (s, 1H), 6.35 (s, 1H), 7.05-7.08 (m,1H), 7.26-7.32 (m, 3H), 7.40-7.45 (m, 2H); ¹³C NMR (CDCl₃) δ 24.04,28.55, 30.45, 45.28, 51.82, 52.27, 53.89, 70.02, 70.16, 79.81, 114.44,116.18, 121.59, 121.98, 122.93, 123.08, 126.64, 129.90, 133.43, 135.50,137.69, 153.70, 154.51, 169.36, 171.49, 172.88.

Step 4: A solution of potassium t-butoxide/THF (1M, 2.4 mL, 2.4 mmol)was added slowly to a stirred solution of tert-butyl5-((2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)isoindoline-2-carboxylate(1.3 g, 2.4 mmol) in THF (20 mL) at 5° C. The reaction mixture wasstirred at 5° C. for 30 minutes then quenched with sat. NH₄Cl (5 mL).The mixture was stirred with CH₂Cl₂ (50 mL) and water (15 mL) andaqueous layer was extracted with CH₂Cl₂ (30 mL). Combined CH₂Cl₂solution was washed with sat. NaHCO₃ (30 mL), water (2×30 mL), and brine(30 mL), and dried. The solvent was removed and the residue was purifiedby chromatography (SiO₂, CH₃OH:CH₂Cl₂ 3:97) to give tert-butyl5-((2-(2,6-dioxo-piperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)isoindoline-2-carboxylate(0.6 g, 50% yield): mp 178-180° C.; ¹H NMR (DMSO-d₆) δ 1.45 (s, 9H),1.96-2.02 (m, 1H), 2.41-2.60 (m, 2H), 2.86-2.91 (m, 1H), 4.28 (d, J=17.4Hz, 1H), 4.38 (d, J=17.4 Hz, 1H), 4.59 (b, 4H), 5.07-5.14 (dd, J=5.1 and13.5 Hz, 1H), 5.24 (s, 2H), 7.31-7.51 (m, 6H), 10.97 (s, 1H); ¹³C NMR(DMSO-d₆) δ 22.34, 28.12, 31.18, 45.08, 51.48, 51.65, 69.42, 78.80,115.01, 115.25, 122.15, 122.88, 126.94, 129.79, 129.95, 133.30, 135.82,136.41, 136.96, 137.44, 138.40, 167.97, 170.96, 172.82; Calcd forC₂₇H₂₉N₃O₆: C, 65.98; H, 5.95; N, 8.55; Found: C, 65.76; H, 6.10; N,8.33.

5.1303-(4-(BENZO[B]THIOPHEN-3-YLMETHOXY)-1-OXOISOINDOLIN-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: Diisopropyl azodicarboxylate (1.1 g, 5.5 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol), 1-benzothiophen-3-ylmethanol (0.7 g, 4.1 mmol) andtriphenylphosphine-polymer bound (1.8 g, 5.5 mmol) in THF (60 mL) at5-8° C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and solid was washed withCH₂Cl₂ (30 mL). Filtrate was concentrated and the residue was purifiedby chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-(benzo[b]thiophen-3-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1 g, 77%).

Step 2: A solution of potassium t-butoxide/THF (1M, 2.3 mL, 2.3 mmol)was added to a stirred solution of methyl5-amino-4-(4-(benzo[b]thiophen-3-ylmethoxy)-1-oxoisoindolin-2-yl]-5-oxopentanoate(1.0 g, 2.3 mmol) in THF (30 mL) at 5° C. The mixture was stirred at 5°C. for 10 minutes then warmed to room temperature for 2 hours. Thereaction mixture was cooled in an ice bath and quenched with 1N HCl (10mL). The mixture was stirred with CH₂Cl₂ (50 mL) and water (10 mL) andaqueous layer was extracted with CH₂Cl₂ (30 mL). Combined CH₂Cl₂solution was washed with water (2×40 mL), brine (40 mL) and dried. Thesolvent was removed and the residue was purified by chromatography(SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give3-(4-benzo[b]thiophen-3-ylmethoxy)-1-oxoisoindolin-2yl)-piperidine-2,6-dione(0.3 g, 32% yield): mp231-233° C.; H NMR (DMSO-d₆) δ 1.94-1.98 (m, 1H),2.28-2.58 (m, 2H), 2.85-2.95 (m, 1H), 4.24 (d, J=17.4 Hz, 1H), 4.34 (d,J=17.7 Hz, 1H), 5.06-5.12 (dd, J=5.1 and 13.2 Hz, 1H), 5.52 (s, 2H),7.33-7.52 (m, 5H), 7.92-8.03 (m, 3H), 10.94 (s, 1H); ¹³C NMR (DMSO-d₆) δ22.28, 31.13, 45.04, 51.52, 64.29, 115.05, 115.31, 122.11, 122.96,124.04, 124.64, 126.79, 129.80, 129.93, 131.36, 133.31, 137.71, 139.76,153.34, 167.94, 170.94, 172.78; Calcd for C₂₂H₁₈N₂O₄S+0.5H₂O: C, 63.30;H, 4.61; N, 6.74; S, 7.72; Found: C, 63.85; H, 4.41; N, 6.75; S, 7.96.

5.1313-[4-(2,3-DIHYDRO-BENZOFURAN-2-YLMETHOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer bonded triphenylphosphine (1.6 g, 2.06 mmol, 1.25mmol/g) was added to the stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1, 3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (300 mg, 1.03 mmol) in THF (10 mL) at 0° C. The resultingmixture was stirred at 0° C. for 10 minutes, followed by the addition ofDIAD (412 mg, 2.06 mmol). Ten minutes later,(2,3-Dihydro-benzofuran-2-yl)-methanol (250 mg, 1.66 mmol) was added tothe mixture. The reaction was stirred at room temperature for 7.5 hoursand the reaction was complete. The reaction mixture was filtered, andthe solid was washed with dichloromethane (7×20 mL). The filtrate wasconcentrated and the residue was purified by ISCO chromatography to give4-Carbamoyl-4-[4-(2,3-dihydro-benzofuran-2-ylmethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as an oil (380 mg, 87% yield): LCMS MH=425.

Step 2: KOtBu (100.5 mg, 0.89 mmol) was added to the stirred solution of4-carbamoyl-4-[4-(2,3-dihydro-benzofuran-2-ylmethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (380 mg, 0.89 mmol) in tetrahydrofuran (18 mL) at 0°C. The mixture was stirred at 0° C. for 0.5 hour and the reaction wascomplete. The cold reaction mixture was added by HCl (aq. 0.1N, 10 mL),followed by the addition of dichloromethane (25 mL) and brine (10 mL).The mixture was extracted and organic layer was dried by MgSO₄ andconcentrated under vacuo. The residue was purified by ISCOchromatography to give3-[4-(2,3-dihydro-benzofuran-2-ylmethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (243 mg, 70% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 (acetonitrile/0.1% H₃PO₄):t_(R)=4.32 (98%); mp: 258-260° C.; ¹H NMR (DMSO-d₆) δ 1.90-2.05 (m, 1H,CHH), 2.28-2.46 (m, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.82-2.99 (m, 1H,CHH), 3.04-3.20 (m, 1H, CHH), 3.35-3.43 (m, 1H, CHH), 3.97-4.45 (m, 4H,CHH, CHH, CHH, CHH), 5.03-5.22 (m, 2H, CNH, COH), 6.75 (d, J=7.9 Hz, 1H,Ar), 6.79-6.88 (m, 1H, Ar), 7.02-7.13 (m, 1H, Ar), 7.19-7.37 (m, 3H,Ar), 7.42-7.55 (m, 1H, Ar), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.39, 44.75, 51.52, 70.33, 80.31, 108.89, 114.88, 115.36, 120.29,124.94, 126.61, 127.74, 127.79, 129.72, 129.76, 129.84, 133.24, 153.54,159.08, 167.93, 170.96, 172.81; LCMS MH=393; Anal. Calcd forC₂₂H₂₀N₂O₅+0.3H₂O: C, 66.42; H, 5.22; N, 7.04. Found: C, 66.28; H, 5.12;N, 7.34.

5.1323-(4-(IMIDAZO[1,2-A]PYRIDIN-2-YLMETHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Diisopropyl azodicarboxylate (1.1 g, 5.5 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol), imidazo[1,2-a]pyridin-2-ylmethanol (0.6 g, 4.1 mmol) andtriphenylphosphine-polymer bound (1.8 g, 5.5 mmol) in THF (100 mL) at5-8° C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and solid was washed withmethylene chloride (30 mL). Filtrate was concentrated and the residuewas purified by chromatography (amine column, CH₃OH: CH₂Cl₂ 3: 97) togive methyl 5-amino-4-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-1-oxoisoindo 1 in-2-yl)-5-oxopentanoate (0.5 g, 41% yield): ¹HNMR (DMSO-d₆) δ 1.99-2.28 (m, 4H), 3.50 (s, 3H), 4.41 (d, J=18.0 Hz,1H), 4.51 (d, J=18.0 Hz, 1H), 4.71-4.75 (m, 1H), 5.35 (s, 2H), 6.89 (t,J=6.0 Hz, 1H), 7.18-7.30 (m, 3H), 7.41-7.58 (m, 4H), 8.05 (s. 1H), 8.55(d, J=6.0 Hz, 1H).

Step 2: Potassium t-butoxide/THF (1M, 1.1 mL, 1.1 mmol) was added to astirred solution of methyl5-amino-2-(4-(imidazo[1,2-a]pyridine-2-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.4 g, 1.1 mmol) in THF (30 mL) and DMF (20 mL). The resulting mixturewas stirred at room temperature for 2 hours. The reaction mixture wascooled in an ice bath and quenched with water (30 mL). The mixture wasstirred with methylene chloride (40 mL) and aqueous layer was extractedwith methylene chloride (2×40 mL). Combined organic solution was washedwith water (40 mL) and brine (40 mL), and dried. The solvent was removedand the residue was stirred with water (20 mL). The mixture was filteredand solid was reslurried with methylene chloride (15 mL) to give3-(4-(imidazo[1,2-a]pyridin-2-ylmethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.1 g, 28%) as awhite solid: mp 222-224° C.; ¹H NMR (DMSO-d₆) δ 1.96-2.01 (m, 1H),2.35-2.51 (m, 2H), 2.58-2.91 (m, 1H), 4.26 (d, J=17.4 Hz, 1H), 4.36 (d,J=17.4 Hz, 1H), 5.08-5.14 (dd, J=5.1 and 13.5 Hz, 1H), 5.36 (s, 2H),6.87-6.91 (dt, J=0.9 and 6.6 Hz, 1H), 7.21-7.55 (m, 5H), 8.03 (s, 1H),8.51-8.53 (dd, J=0.9 and 6.6 Hz, 1H), 10.97 (s, 1H); ¹³C NMR (DMSO-d₆) δ22.35, 31.17, 45.06, 51.54, 64.63, 111.79, 112.14, 115.01, 115.18,116.65, 124.90, 126.95, 129.78, 129.84, 133.26, 141.54, 144.28, 153.45,167.98, 170.96, 172.81; Calcd. For C₂₁H₁₈N₄O₄+0.25H₂O: C, 63.87, H,4.72; N, 14.19; Found: C, 63.99, H, 4.60; N, 14.20.

5.1333-(4-(IMIDAZO[1,2-A]PYRIDIN-6-YLMETHOXY)-1-OXOISOINDOLIN-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: Diisopropyl azodicarboxylate (1.3 g, 6.2 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanonate (0.9 g,3.1 mmol), imidazo[1,2-a]pyridine-6-ylmethanol (0.7 g, 4.6 mmol) andtriphenylphosphine-polymer bound (2.1 g, 6.2 mmol) in THF (70 mL) at5-8° C. After addition, the mixture was stirred at 5° C. for 5 minutesthen warmed to room temperature overnight. The reaction mixture wasfiltered and solid was washed with CH₂Cl₂ (30 mL). Filtrate wasconcentrated and the residue was purified by chromatography (SiO₂,CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.8 g, 65%).

Step 2: A solution of potassium t-butoxide/THF (1M, 2.0 mL, 2.0 mmol)was added to a stirred solution of methyl5-amino-4-(4-(imidazo[1,2-a]pyridin-6-ylmryhoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.8 g, 2.0 mmol) in THF (50 mL) at 5° C. The mixture was stirred at 5°C. for 10 minutes then warmed to room temperature for 2 hours. Thereaction mixture was cooled in an ice bath and quenched with water (30mL). The mixture was extracted with CH₂Cl₂ (3×30 mL) and combined CH₂Cl₂solution was washed with brine (40 mL) and dried. The solvent wasremoved and the residue was purified by chromatography (SiO₂, CH₃OH:CH₂Cl₂ 3: 97) to give3-(4-(imidazo[1,2-a]pyridin-6-ylmethoxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione(0.25 g, 32% yield): mp 270-272° C.; ¹H NMR (DMSO-d₆) δ 2.00 (m, 1H),2.26-2.53 (m, 2H), 2.85-2.97 (m, 1H), 4.29 (d, J=17.4 Hz, 1H), 4.39 (d,J=17.7 Hz, 1H), 5.08-5.14 (dd, J=5.1 and 13.2 Hz, 1H), 5.26 (s, 2H),7.28-7.41 (m, 3H), 7.51 (t, J=7.8 Hz, 1H), 7.58-7.61 (m, 2H), 7.97 (s,1H), 8.72 (s, 1H), 10.97 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.35, 31.15,45.04, 51.54, 67.26, 113.45, 115.07, 115.45, 116.84, 120.99, 125.10,125.95, 129.83, 130.01, 133.34, 133.44, 144.01, 153.26, 167.94, 170.94,172.80; Calcd for C₂₁H₁₈N₄O₄+0.15H₂O: C, 64.19; H, 4.69; N, 14.25;Found: C, 64.10; H, 4.60; N, 14.32.

5.1343-(4-(BENZO[B]THIOPHEN-3-YLMETHOXY)-1-OXOISOINDOLIN-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: Diisopropyl azodicarboxylate (1.1 g, 5.47 mmol) was added to astirred solution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol), 1-benzothiophen-5-ylmethanol (0.7 g, 4.1 mmol) andtriphenylphosphine-polymer bound (1.8 g, 5.5 mmol) in THF (60 mL) at5-8° C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and solid was washed withCH₂Cl₂ (30 mL). Filtrate was concentrated and the residue was purifiedby chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-(benzo[b]thiophen-5-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.8 g, 56%).

Step 2: A solution of potassium t-butoxide/THF (I M, 2.3 ml, 2.3 mmol)was added to a stirred solution of methyl5-amino-4-(4-(benzo[b]thiophen-5-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.0 g, 2.3 mmol) in THF (30 mL) at 5° C. The mixture was stirred at 5°C. for 10 minutes then warmed to room temperature for 2 hours. Thereaction mixture was cooled in an ice bath and quenched with 1N HCl (10mL). The mixture was diluted with CH₂Cl₂ (50 mL) and water (10 mL). Theaqueous layer was extracted with CH₂Cl₂ (30 mL) and combined CH₂Cl₂solution was washed with water (2×40 mL) and brine (40 mL), and dried.The solvent was removed and the residue was purified by chromatography(SiO₂, CH₃OH: CH₂C₂ 3: 97) to give3-(4-benzo[b]thiophen-5-ylmethoxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione(0.4 g, 36% yield): mp 213-215° C.; ¹H NMR (DMSO-d₆) δ 1.95-2.01 (m,1H), 2.36-2.52 (m, 2H), 2.85-2.95 (m, 1H), 4.30 (d, J=17.4 Hz, 1H), 4.40(d, J=17.4 Hz, 1H), 5.08-5.14 (dd, J=5.1 and 13.5 Hz, 1H), 5.37 (s, 2H),7.31-7.37 (2d, J=8.1 and 7.5 Hz, 2H), 7.46-7.51 (m, 3H), 7.79 (d, J=5.4Hz, 1H), 8.00-8.04 (m, 2H), 10.97 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.33,31.17, 45.09, 51.57, 69.67, 115.05, 115.23, 122.68, 122.77, 123.89,124.11, 128.09, 129.79, 129.97, 132.84, 133.31, 138.75, 139.50, 153.46,167.98, 170.95, 172.80; Calcd for C₂₂H₁₈N₂O₄S: C, 65.01; H, 4.46; N,6.89; S, 7.89; Found: C, 64.66; H, 4.07; N, 6.76; S, 7.87.

5.1353-(1-OXO-4-(QUINOLIN-6-YLMETHOXY)-ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: DIBAL/toluene (1M, 16 mL, 16 mmol) was added slowly to a stirredsolution of methyl quinoline-6-carboxylate (1.0 g, 5.3 mmol) in THF (30mL) at −60° C. The resulting solution was stirred at −20° C. for 1.5hours and then carefully quenched with water (15 mL). The mixture wasconcentrated and the residue was stirred in EtOAc (80 mL) and sat.NaHCO₃ (20 mL). The mixture was filtered and aqueous layer was extractedwith EtOAc (2×30 mL). Combined EtOAc solution was washed with water (30mL) and brine (30 mL) and dried (MgSO₄). The solvent was removed and theresidue was purified by chromatography (SiO₂, EtOAc: CH₂Cl₂ 1: 1) togive quinolin-6-yl-methanol (0.5 g, 62% yield): ¹H NMR (DMSO-d₆) δ 4.69(d, J=5.1 Hz, 2H), 5.42 (t, J=5.4 Hz, 1H), 7.49-7.53 (dd, J=4.5 and 8.4Hz, 1H), 7.69-7.72 (dd, J=1.8 and 8.7 Hz, 1H), 7.88 (d, J=0.9 Hz, 1H),7.96 (d, J=8.7 Hz, 1H), 8.32-8.36 (dd, J=0.9 and 8.4 Hz, 1H), 8.85-8.87(dd, J=1.8 and 4.2 Hz, 1H).

Step 2: Diisopropyl azodicarboxylate (0.7 g, 3.6 mmol) was added to astirred suspension of triphenylphosphine-polymer bound (3 g, 3.8 mmon)in THF (40 mL) at 3-6° C. After stirred for 10 minutes at 3° C., asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.7 g, 2.4mmol) and quinolin-6-yl-methanol (0.5 g, 3.1 mmol) in THF (40 mL) wasadded slowly at 3-7° C. The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was filtered and solid waswashed with CH₂Cl₂ (30 mL). Filtrate was concentrated and the residuewas purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 5: 95) to givemethyl5-amino-5-oxo-4-(1-oxo-4-(quinolin-6-ylmethoxy)-isoindolin-2-yl)pentanoate(0.5 g, 46%).

Step 3: KO-t-Bu/THF (1M, 1.1 mL, 1.1 mmol) was added slowly to a stirredsolution of methyl5-amino-5-oxo-4-(1-oxo-4-(quinolin-6-ylmethoxy)isoindolin-2-yl)pentanoate(0.5 g, 1.1 mmol) at 5° C. The reaction mixture was stirred 30 minutesat 5° C. then quenched with sat. NH₄Cl (5 mL). The mixture was stirredwith CH₂Cl₂ (50 mL) and sat. NaHCO₃ (15 mL). The aqueous layer wasextracted with CH₂Cl₂ (30 mL) and combined CH₂Cl₂ solution was washedwith water (20 mL) and brine (30 mL), and dried (MgSO₄). The solvent wasremoved and the residue was stirred with CH₂Cl₂ (3 mL) and ether (3 mL).Solid was collected to give3-(1-oxo-4-(quinolin-6-ylmethoxy)isoindolin-2-yl)piperidine-2,6-dione(0.3 g, 60% yield): mp 267-269° C.; ¹H NMR (DMSO-d6) δ 1.97-2.02 (m,1H), 2.42-2.62 (m, 2H), 2.86-2.92 (m, 1H), 4.35 (d, J=17.4 Hz, 1H), 4.45(d, J=17.4 Hz, 1H), 5.10-5.16 (dd, J=5.1 and 13.2 Hz, 1H), 5.47 (s, 2H),7.33-7.37 (m, 2H), 7.47-7.57 (m, 2H), 7.86-7.89 (dd, J=1.8 and 8.7 Hz,1H), 8.04-8.09 (m, 2H), 8.38-8.41 (dd, J=0.9 and 8.4 Hz, 1H), 8.90-8.92(dd, J=1.8 and 4.2 Hz, 1H), 10.98 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.36,31.17, 45.10, 51.58, 69.27, 115.08, 115.39, 121.74, 126.41, 127.60,129.02, 129.22, 129.84, 120.02, 133.37, 134.96, 136.01, 147.36, 150.71,153.40, 167.97, 170.98, 172.82; Calcd for C₂₃H₁₉N₃O₄+0.2H₂O: C, 68.21;H, 4.83; N, 10.37; Found: C, 68.04; H, 4.78; N, 10.10.

5.1363-(4-(NAPHTHALEN-2-YLMETHOXY)-1-OXOISOINDOLIN-2-YL)-PIPREIDINE-2,6-DIONE

Step 1: Diisopropyl azodicarboxylate (0.8 g, 4.1 mmol) was added slowlyto a stirred suspension of triphenylphosphine-polymer bound (3.0 g, 4.5mmol) in THF (40 mL) at 3-6° C. After stirred at 3° C. for 10 minutes, asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol), 2-naphthalene-methanol (0.7 g, 4.1 mmol) and triethylamine (0.4g, 4.1 mmol) in THF (40 mL) was added at 3-6° C. After addition, themixture was stirred at room temperature overnight. The reaction mixturewas filtered and solid was washed with CH₂Cl₂ (30 mL). Filtrate wasconcentrated and the residue was purified by chromatography (SiO₂,CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-(naphthalen-2-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.6 g, 50%).

Step 2: A solution of potassium t-butoxide/THF (1M, 1.4 mmol) was addedslowly to a stirred solution of methyl5-amino-4-(4-(naphthalen-2-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.6 g, 1.4 mmol) in THF (20 mL) at 5° C. The resulting solution wasstirred at 5° C. for 30 minutes then quenched with sat. NH₄Cl (5 mL).The mixture was stirred with CH₂Cl₂ (40 mL) and water (15 mL). Theaqueous layer was extracted with CH₂Cl₂ (40 mL) and combined CH₂Cl₂solution was washed with water (20 mL) and brine (20 mL), and dried. Thesolvent was removed and the residue was purified by chromatography(SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give3-(4-(naphthalen-2-ylmethoxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione(0.2 g, 36% yield): mp 277-279° C.; ¹H NMR (DMSO-d₆) δ 1.97-2.02 (m,1H), 2.42-2.61 (m, 2H), 2.85-2.95 (m, 1H), 4.33 (d, J=17.4 Hz, 1H), 4.43(d, J=17.4 Hz, 1H), 5.09-5.15 (dd, J=5.1 and 13.2 Hz, 1H), 5.42 (s, 2H),7.32-7.39 (m, 2H), 7.46-7.56 (m, 3H), 7.60-7.64 (m, 1H), 7.91-7.96 (m,3H), 8.02 (s, 1H), 10.97 9 s, 1H); ¹³C NMR (DMSO-d₆) δ 22.34, 31.17,45.11, 51.58, 69.67, 115.08, 115.29, 125.58, 126.18, 126.31, 127.57,127.77, 128.12, 129.81, 130.00, 132.57, 132.71, 133.34, 134.21, 153.47,167.98, 170.96, 172.81; Calcd for C₂₄H₂₀N₂O₄: C, 71.99; H, 5.03; N,7.00. Found: C, 71.71; H, 5.09; N, 6.93.

5.1373-(4-((2,3-DIHYDRO-1H-INDAN-5-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: Diisopropyl azodicarboxylate (0.8 g, 4.1 mmol) was added to astirred suspension of triphenylphosphine-polymer bound (3.5 g, 4.4 mmol)in THF (40 mL) at 3-5° C. After stirred at 3° C. for 10 minutes, asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol) and 5-hydroxymethylindane (0.5 g, 3.6 mmol) in THF (40 mL) wasadded slowly at 3-5° C. The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was filtered and solid waswashed with CH₂Cl₂ (30 mL). Filtrate was concentrated and the residuewas dissolved in CH₂Cl₂ (80 mL) and washed with sat. NaHCO₃ (30 mL),water (2×30 mL) and brine (30 mL), and dried. The solvent was removedand the residue was purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3:97) to give methyl5-amino-4-(4-((2,3-dihydro-1H-indan-5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.7 g, 60% yield): ¹H NMR (CDCl₃) δ 2.05-2.45 (m, 6H), 2.89-2.96 (m,4H), 3.64 (s, 3H), 4.35-4.49 (dd, J=17.4 and 26.4 Hz, 2H), 4.87-4.92(dd, J=6.0 and 8.7 Hz, 1H), 5.10 (s, 2H), 5.37 (s, 1H), 6.33 (s, 1H),7.08-7.28 (m, 4H), 7.37-7.44 (m, 2H).

Step 2: A solution of potassium t-butoxide/THF (1M, 1.5 mL, 1.5 mmol)was added slowly to a stirred solution of methyl5-amino-4-(4-((2,3-dihydro-1H-indan-5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.6 g, 1.5 mmol) in THF (20 mL) at 5° C. The resulting solution wasstirred at 5° C. for 30 minutes then quenched with sat. NH₄Cl (5 mL).The mixture was stirred with CH₂Cl₂ (50 mL) and water (15 mL) andaqueous layer was extracted with CH₂Cl₂ (30 mL). Combined CH₂Cl₂solution was washed with water (20 mL) and brine (20 mL), and dried. Thesolvent was removed and solid residue was stirred with acetone (10 mL)to give3-(4-((2,3-dihydro-1H-indan-5-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.3 g, 58% yield): mp 216-218° C.; ¹H NMR (DMSO-d₆) δ 1.96-2.08 (m,3H), 2.41-2.60 (m, 2H), 2.82-2.96 (m, 5H), 4.26 (d, J=17.7 Hz, 1H), 4.36(d, J=17.7 Hz, 1H), 5.07-5.13 (dd, J=5.1 and 13.5 Hz, 1H), 5.19 (s, 2H),7.23-7.25 (m, 2H), 7.30-7.33 (m, 3H), 7.47 (t, J=7.8 Hz, 1H), 10.86 (s,1H); ¹³C NMR (DMSO-d₆) δ 22.31, 25.05, 31.17, 32.00, 32.17, 45.08,51.56, 69.76, 114.98, 115.11, 123.77, 124.15, 125.84, 129.76, 129.92,133.26, 134.32, 143.60, 143.98, 153.50, 167.99, 170.96, 172.81; Calcdfor C₂₃H₂₂N₂O₄+0.3H₂O: C, 69.79; H, 5.75; N, 7.08; Found: C, 69.72; H,5.67; N, 6.91.

5.1383-(4-(BENZO[D]OXAZOL-5-YLMETHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A mixture of 5-methylbenzo[d]oxazole (2 g, 15 mmol), NBS (2.67g, 15 mmol) and benzoyl peroxide (50 mg, 0.21 mmol) was heated to refluxin CCl₄ (50 mL) overnight. The mixture was cooled to room temperature,and the resulting precipitate was removed by filtration. The filtratewas concentrated under reduced pressure and the residue was purified byISCO (40 g column, EtOAc/hexanes gradient from 0% to 20% in 40 min) togive 5-(bromomethyl)benzo[d]oxazole (1.6 g, 50% yield); ¹H NMR(DMSO-d₆): 4.88 (s, 2H, CH₂), 7.55 (dd, J=1.7, 8.5 Hz, 1H, Ar), 7.77 (d,J=8.5 Hz, 1H, Ar), 7.91 (d, J=1.5 Hz, 1H, Ar), 8.79 (s, 1H, Ar).

Step 2: To a suspension of potassium carbonate (189 mg, 1.37 mmol) inDMF (5 mL), were added 5-(bromomethyl)benzo[d]oxazole (261 mg, 1.23mmol) and methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (400 mg, 1.37mmol). The formed mixture was stirred at room temperature over weekend.Additional 5-(bromomethyl)benzo[d]oxazole (87 mg, 0.41 mmol) was added,and the mixture was stirred at room temperature overnight. The reactionwas quenched with water (40 mL) at 0° C., the product was extracted withethyl acetate (3×30 mL), and the combined organic layers were washedwith water (20 mL) and brine (20 mL). The solvent was evaporated undervacuum and the product was purified with ISCO (40 g column, MeOH/CH₂Cl₂gradient from 0% to 5% in 40 min) to give methyl5-amino-4-(4-(benzo[d]oxazol-5-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(440 mg, 76% yield); ¹H NMR (DMSO-d₆): 1.82-2.37 (m, 4H, CH₂, CH₂), 3.50(s, 3H, CH₃), 4.34-4.64 (m, 2H, CH₂), 4.67-4.83 (m, 1H, CH), 5.38 (s,2H, CH₂), 7.18 (s, 1H, NHH), 7.26-7.41 (m, 2H, Ar), 7.45 (d, J=7.7 Hz,1H, Ar), 7.59 (dd, J=1.4, 8.4 Hz, 2H, Ar), 7.81 (d, J=8.3 Hz, 1H, Ar),7.96 (d, J=0.9 Hz, 1H, NHH), 8.78 (s, 1H, Ar).

Step 3: To a mixture of methyl5-amino-4-(4-(benzo[d]oxazol-5-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(450 mg, 1.06 mmol) in THF (20 mL), was added potassium tert-butoxide(119 mg, 1.06 mmol) at 0° C. The formed mixture was warm up to roomtemperature and stirred overnight. Additional potassium tert-butoxide(48 mg, 0.43 mmol) was added, and the mixture was stirred at roomtemperature for 3 hours. The reaction was quenched with acetic acid (1mL) at 0° C., the solvent was evaporated to dryness, the residue wastaken in actonitrile (5 mL), and water (10 mL) was added dropwise, thensaturated sodium bicarbonate was added to adjust pH to 7. The mixturewas stirred overnight, the resulting solid was filtered and resulrriedwith acetonitrile (3 mL) to give3-(4-(benzo[d]oxazol-5-ylmethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (180 mg, 43% yield); mp: 209-211° C.; ¹H NMR (DMSO-d₆):1.89-2.07 (m, 1H, CHH), 2.35-2.48 (m, 1H, CHH), 2.60 (br. s., 1H, CHH),2.82-3.02 (m, 1H, CHH), 4.22-4.54 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2Hz, 1H, CH), 5.38 (s, 2H, CH₂), 7.35 (dd, J=7.6, 10.6 Hz, 2H, Ar),7.44-7.55 (m, 1H, Ar), 7.58 (dd, J=1.5, 8.5 Hz, 1H, Ar), 7.80 (d, J=8.5Hz, 1H, Ar), 7.95 (d, J=0.9 Hz, 1H, Ar), 8.78 (s, 1H, Ar), 10.97 (s, 1H,NH); ¹³C NMR (DMSO-d₆): 22.33, 31.16, 45.10, 51.58, 69.32, 111.09,115.03, 115.29, 119.48, 125.56, 129.78, 130.02, 133.33, 133.40, 139.83,149.05, 153.35, 154.75, 167.99, 170.95, 172.81; LCMS MH=392; HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75acetonitrile/0.1% H₃PO₄ t_(R)=4.59 (98.54%); Anal. Calcd forC₂₁H₁₇N₃O₅+0.3H₂O: C, 63.57; H, 4.47; N, 10.59; Found: C, 63.54; H,4.31; N, 10.58.

5.1393-(4-(ISOINDOLIN-5-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONEHYDROCHLORIDE

A solution of tert-butyl5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)isoindoline-2-carboxylate(0.6 g, 1.3 mmol) in THF (20 mL) was treated with HCl/ether (2M, 1.9 mL,3.8 mmol) and stirred at room temperature for 8 hours. Ether (10 mL) wasadded and solid was collected. Solid was reslurried with CH₂Cl₂ (15 mL)to give3-(4-(isoindolin-5-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride (0.5 g, 88% yield): mp270-272° C.; ¹H NMR (DMSO-d₆) δ1.97-2.00 (m, 1H), 2.41-2.61 (m, 2H), 2.87-2.93 (m, 1H), 4.28 (d, J=15Hz, 1H), 4.39 (d, J=18 Hz, 1H), 4.50 (s, 4H), 5.08-5.14 (dd, J=6 and 15Hz, 1H), 5.28 (s, 2H), 7.32-7.52 (m, 6H), 10.01 (s, 2H), 10.98 (s, 1H);¹³C NMR (DMSO-d₆) δ 22.35, 31.18, 45.08, 49.73, 49.79, 51.57, 69.19,115.01, 115.33, 122.14, 123.01, 127.77, 129.81, 129.93, 133.32, 134.89,135.47, 136.95, 153.31, 167.95, 170.96, 172.83; Calcd forC₂₂H₂₃N₃O₄Cl+0.5H₂O: C, 60.48; H, 5.31; N, 9.62; Cl, 8.11; Found: C,60.11; H, 5.21; N, 9.38; Cl, 8.27.

5.1403-(4-((1H-BENZO[D]IMIDAZOL-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONEHYDROGEN CHLORIDE

Step 1: To a stirred solution of 2-(chloromethyl)-1H-benzo[d]imidazole(1 g, 6.00 mmol) in DMF (10 ml, 129 mmol), was added di-tert-butyldicarbonate (1.375 g, 6.30 mmol) at room temperature. After about 10minutes, cat amounts of DMAP (0.05 g, 0.409 mmol) was added to the rxnmixture. The resulting solution was stirred for an additional 5 minutesat room temperature (LCMS indicated reaction has gone to completion) andthe mixture was incubated at 4° C. overnight. The reaction mixture wasconcentrated in vacuo to an oil which was diluted with EtOAc (˜200 mL),transferred to a separatory funnel, and washed with aqueous 1M KH₂PO₄(pH-5, 2×50 mL). The organic layer was washed with brine, dried(Na₂SO₄), and concentrated in vacuo. The residue was dried in a vacuumoven to give tert-butyl2-(chloromethyl)-1H-benzo[d]imidazole-1-carboxylate as an amber oil (1.6g, 97% yield). The oil was used in the next step without furtherpurification. ¹H NMR (DMSO-d₆) δ 1.59-1.76 (m, 9H, tBu), 5.13 (s, 2H,CH₂), 7.33-7.51 (m, 2H, Ar), 7.62-7.84 (m, 1H, Ar), 7.87-8.10 (m, 1H,Ar); ¹³C NMR (DMSO-d₆) δ 27.36, 86.28, 114.88, 119.99, 124.52, 125.61,132.77, 141.16, 147.47, 150.23; One carbon signal (CH₂Cl) is notobserved due to overlap with DMSO-d₆; confirmed by HMQC; LCMS MH=267,269 (mainly see -Boc fragmentation

Step 2: tert-Butyl5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (500 mg,1.495 mmol) and potassium carbonate (227 mg, 1.645 mmol) were suspendedin DMF (7 mL) at room temperature. To the stirred mixture at roomtemperature, was added tert-butyl2-(chloromethyl)-1H-benzo[d]imidazole-1-carboxylate (439 mg, 1.645 mmol)as a solution in DMF (3 mL). The resulting suspension was stirred atroom temperature for about 15 hours. The crude reaction mixture waspartitioned between EtOAc (150 mL) and water (˜50 mL). The organic layerwas washed with brine (50 mL), dried (Na₂SO₄), and concentrated invacuo. The oily residue was diluted with dichloromethane (˜10 mL),concentrated to dryness (2× from dichloromethane) and the resulting oilwas placed in a vacuum oven at 40° C. for several hours to affordtert-butyl2-((2-(5-amino-1-tert-butoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)-1H-benzo[d]imidazole-1-carboxylate(1 g) as a tan oil, which was used in the next step without furtherpurification. LCMS MH (-Boc)=465.

Step 3: tert-Butyl2-((2-(5-amino-1-tert-butoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)-1H-benzo[d]imidazole-1-carboxylate(844 mg, 1.495) was dissolved in THF (10 ml, 122 mmol). To the stirredsolution at room temperature, was added KOtBu (2 ml, 2.0 mmol, 1.0 M inTHF) in a rapid dropwise fashion via syringe and reaction progress wasclosely monitored by LCMS. After about 50 minutes, additional KOtBu (1mL, 1 mmol) was added, and the mixture stirring was continued at roomtemperature for about 15 minutes. The reaction mixture was stored at−20° C. overnight. The following morning, additional KOtBu (0.5 mL, 5mmol) was added, followed by another treatment of KOtBu (0.5 mL, 0.5mmol) after 3 hours. After about 80 minutes, the reaction mixture wastransferred to a solution of 2 N HCl in Et₂O (50 mL). The resulting paleyellow slurry was stirred at room temperature. After about 1 hour, theslurry was filtered and the solid was washed with additional Et₂O andthen suction dried on filter funnel. Oven drying gave ˜1 g of crudeproduct as a tan solid. The solid was dissolved in DMF/water (10 mL/3mL), sonicated and then filtered. The filtrate was purified by injectiononto a C-18 preparatory HPLC column. The product was eluted with anacetonitrile/water gradient (0.1% formic acid in both mobile phases, 5%to 30% MeCN over 12 minutes) and fractions were collected by masstrigger. The desired fractions were combined and concentrated in vacuoto give a solid residue which was redissolved in 1 N HCl/acetonitrile(˜1: 1, 40 mL). The mixture was concentrated in vacuo and the solid wastransferred to a scintillation vial. The suspension was frozen andlyophilized to give and off-white solid (145 mg). This solid wasslurried in water (5 mL), and the mixture was stirred for several hoursthen filtered. The solid was suction dried and then stored in vacuumoven overnight to give3-(4-((1H-benzo[d]imidazol-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride as a white solid (90 mg, 15% yield). HPLC: Waters SymmetryC₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 13/87 acetonitrile/0.1% H₃PO₄,4.01 min (96.6%); mp: 229-231° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.12 (m, 1H,CHH), 2.32-2.47 (m, 1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.84-3.04 (m, 1H,CHH), 4.41 (d, J=17.6 Hz, 1H, CHH), 4.55 (d, J=17.6 Hz, 1H, CHH), 5.16(dd, J=5.0, 13.3 Hz, 1H, CH), 5.73 (s, 2H, CH₂), 7.29-7.65 (m, 5H, Ar),7.68-7.85 (m, 2H, Ar), 11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.49,31.18, 45.13, 51.58, 62.19, 114.56, 114.93, 116.34, 124.67, 129.97,130.21, 133.50, 133.55, 149.24, 152.50, 167.74, 170.99, 172.81; LCMSMH=391; Anal Calcd for C₂₁H₁₈N₄O₄+0.76 HCl+3.4H₂O: C, 52.62; H, 5.37; N,11.69; Cl, 5.62; Found: C, 52.72; H, 4.98; N, 11.33; Cl, 5.45.

5.1413-(4-(BENZO[D]THIAZOL-2-YLMETHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Diisopropyl azodicarboxylate (1.3 g, 6.2 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.9 g, 3.1mmol), 1,3-benzothiazole-2-methanol (0.8 g, 4.7 mmol) andtriphenylphosphne-polymer bound (2.1 g, 6.2 mmol) in THF (80 mL) at 5-8°C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and the solid was washedwith methylene chloride (20 mL). Filtrate was concentrated and theresidue was purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) togive methyl5-amino-4-(4-benzo[d]ythiazol-2-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.6 g, 42%).

Step 2: Potassium t-butoxide (0.2 g, 1.4 mmol) was added to a stirredsolution of methyl5-amino-4-(4-benzo[d]triazol-2-ylmethoxy)1-oxoisoindolin-2-yl)-5-oxopentanoate(0.6 g, 1.4 mmol) in THF (40 mL) at 5° C. The mixture was stirred at 5°C. for 10 minutes then warmed to room temperature for 2 hours. Thereaction mixture was cooled in an ice bath and quenched with 4N HCl (3mL). The mixture was diluted with CH₂Cl₂ (80 mL) and washed with water(20 mL), brine (20 mL) and dried. The solvent was removed and theresidue was stirred with CH₂Cl₂ (10 mL) to give 0.4 g of solid. Thesolid was reslurried with hot methanol (15 mL) to give3-(4-(benzo[d]thiazol-2-ylmethoxy)-1-osoisoindolin-2-yl)piperidine-2,6-dione(0.35 g, 63% yield): mp 253-255° C.; ¹H NMR (DMSO-d₆) δ 1.99-2.04 (m,1H), 2.45-2.62 (m, 2H), 2.86-2.94 (m, 1H), 4.39 (d, J=17.4 Hz, 1H), 4.47(d, J=17.7 Hz, 1H), 5.11-5.17 (dd, J=5.1 and 13.2 Hz, 1H), 5.76 (s, 2H),7.32-7.75 (m, 5H), 8.02-8.05 (dd, J=0.6 and 8.1 Hz, 1H), 8.11-8.14 (dd,J=0.6 and 7.8 Hz, 1H), 11.00 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.44, 31.28,45.10, 51.73, 67.53, 115.41, 116.24, 122.48, 122.86, 125.52, 126.47,130.07, 133.63, 134.47, 152.58, 152.72, 167.89, 171.07, 172.94; Calcd.For C₂₁H₁₇N₃O₄S: C, 61.91; H, 4.21; N, 10.31; S, 7.87; Found: C, 61.76;H, 4.01; N, 10.24; S, 7.85.

5.1423-(4-(BENZOFURAN-5-YLMETHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2-6-DIONE

Step 1: A solution of 1-benzofuran-5-carboxylic acid (1.0 g, 6.2 mmol)and trimethyl borate (5 mL) in THF (20 mL) was stirred for 10 minutes.BH₃(CH₃)₂S/THF (2M, 3.7 mL, 7.4 mmol) was added dropwise. The resultingmixture was stirred at room temperature overnight. The reaction mixturewas quenched with methanol (5 mL) and concentrated. The residue wasdissolved in methylene chloride (75 mL) and washed with water (25 mL)and brine (25 mL) and dried. The solvent was removed to givebenzofuran-5-methanol (2.6 g, 95%).

Step 2: Diisopropyl azodicarboxylate (1.4 g, 6.8 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0 g, 3.4mmol), benzofuran-5-methanol (0.8 g, 5.1 mmol) andtriphenylphosphine-polymer bound (2.3 g, 6.8 mmol) in THF (80 mL) at3-6° C. After addition, reaction mixture was stirred at room temperatureovernight. The reaction mixture was filtered and solid was washed withmethylene chloride (20 mL). Filtrate was concentrated and the residuewas purified by chromatography (SO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-(benzofuran-5-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.9 g, 63% yield): ¹H NMR (DMSO-d₆) δ 1.09-1.30 (m, 1H), 2.08-2.25 (m,3H), 3.49 (s, 3H), 4.43 (d, J=17.7 Hz, 1H), 4.50 (d, J=17.6 Hz, 1H),4.71-4.75 (dd, J=5.0 and 10.4 Hz, 1H), 5.33 (s, 2H), 6.98-6.99 (dd,J=1.0 and 2.2 Hz, 1H), 7.18 (s, 1H), 7.27-7.35 (m, 2H), 7.43-7.48 (m,2H), 7.58-7.79 (m, 2H), 8.01 (s, 1H), 8.02 (s, 1H).

Step 3: Potassium t-butoxide (0.3 g, 2.1 mmol) was added to a stirredsolution of methyl5-amino-4-(4-benzofuran-5-ylmethoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoat(0.9 g, 2.1 mmol) in THF (40 mL) at 5° C. The reaction mixture wasstirred at 5° C. for 10 minutes then warmed to room temperature for 2hours. The reaction mixture was cooled in an ice bath and quenched with4N HCl (3 mL). The mixture was diluted with methylene chloride (80 mL)and washed with water (20 mL) and brine (20 mL) and dried. The solventwas removed and the residue was purified by chromatography (SiO₂, CH₃OH:CH₂Cl₂ 3: 97) to give3-(4-(benzofuran-5-ylmethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.5 g, 57%) as a white solid: mp 168-170° C.; ¹H NMR (DMSO-d₆) δ1.97-2.00 (m, 1H), 2.42-2.59 (m, 2H), 2.90-2.91 (m, 1H), 4.28 (d, J=17.4Hz, 1H), 4.39 (d, J=17.4 Hz, 1H), 5.08-5.14 (dd, J=5.4 and 13.5 Hz, 1H),5.33 (s, 2H), 6.97-6.98 (dd, J=0.9 and 2.1 Hz, 1H), 7.31-7.51 (m, 4H),7.60 (d, J=8.4 Hz, 1H), 7.79 (d, J=0.9 Hz, 1H), 8.0 (d, J=2.1 Hz, 1H),10.97 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.32, 31.16, 45.09, 51.56, 69.75,106.70, 111.23, 115.03, 115.18, 120.79, 124.40, 127.28, 129.78, 129.95,131.25, 133.28, 146.55, 153.49, 153.99, 168.00, 170.96, 172.81; Calcd.For C₂₂H₁₈N₂O₅+0.2H₂O: C, 67.07; H, 4.71; N, 7.11; Found: C, 67.05; H,4.57; N, 6.97.

5.1433-(1-OXO-4-(QUINOLIN-2-YLMETHOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A solution of 2-quinoline carboxaldehyde (1.0 g, 6.4 mmol) inreagent alcohol (40 mL) was cooled in dry ice/acetone bath to −60° C.LiBH₄/THF (2M, 3.8 mL, 7.6 mmol) was added dropwise at −60° C. Thereaction mixture was stirred at −60° C. for 1 hour then quenched withwater (10 mL). The mixture was concentrated and the residue wasdissolved in EtOAc (60 mL). EtOAc solution was washed with brine (35 mL)and dried. The solvent was removed to give quinolin-2-ylmethanol (0.9 g,89%).

Step 2: Diisopropyl azodicarboxylate (1.4 g, 6.8 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.0 g, 3.4mmol), quinolin-2-ylmethanol (0.9 g, 5.7 mmol) andtriphenylphosphine-polymer bound (2.3 g, 6.8 mmol) in THF (80 mL) at5-8° C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and solid was washed withmethylene chloride (25 mL). Filtrate was concentrated and the residuewas purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to givemethyl5-amino-5-oxo-4-(1-oxo-4(quinolin-2-ylmethoxy)isoindolin-2-yl)pentanoate(0.7 g, 47% yield): ¹H NMR (DMSO-d₆) δ 2.08-2.31 (m, 4H), 3.51 (s, 3H),4.54 (d, J=17.4 Hz, 1H), 4.61 (d, J=17.6 Hz, 1H), 4.73-4.78 (dd, J=5.0and 10.4 Hz, 1H), 5.52 (s, 2H), 7.21 (s, 1H), 7.29-7.32 (m, 2H), 7.45(t, J=7.8 Hz, 1H), 7.60-7.65 (m, 2H), 7.73-7.82 (m, 2H), 7.99-8.05 (t,J=8.4 Hz, 2H), 8.42 (d, J=8.5 Hz, 1H); ¹³C NMR (DMSO-d₆) δ 24.83, 30.34,44.82, 51.25, 53.42, 71.05, 114.79, 115.44, 119.44, 126.63, 127.21,127.94, 128.51, 129.63, 129.90, 130.29, 133.54, 137.16, 146.90, 153.23,157.13, 167.81, 171.74, 172.48.

Step 3: Potassium t-butoxide (0.2 g, 1.6 mmol) was added to a stirredsolution of methyl5-amino-5-oxo-4-(1-oxo-4-(quinolin-2-ylmethoxy)isoindolin-2-yl)pentanoate(0.7 g, 1.6 mmol) in THF (50 mL) at 5° C. The reaction mixture wasstirred at 5° C. for 10 minutes then warmed to room temperature for 2hours. The reaction mixture was cooled in an ice bath and quenched with4N HCl (3 mL). The mixture was diluted with methylene chloride (80 mL)and washed with saturated NaHCO₃ (25 mL). The organic layer was washedwith water (40 mL) and brine (40 mL) and dried. The solvent was removedand solid residue was slurried with CH₂Cl₂ (20 mL) to give3-(1-oxo-4-(quinolin-2-ylmethoxy)isoindolin-2-yl)piperidine-2,6-dione(0.2 g, 26%) as a white solid: mp269-271° C.; ¹H NMR (DMSO-d₆) δ1.99-2.04 (m, 1H), 2.44-2.63 (m, 2H), 2.88-2.93 (m, 1H), 4.39 (d, J=17.5Hz, 1H), 4.50 (d, J=17.5 Hz, 1H), 5.11-5.17 (dd, J=5.1 and 13.3 Hz, 1H),5.25 (s, 2H), 7.32-7.36 (dd, J=2.6 and 6.9 Hz, 2H), 7.48 (t, J=7.8 Hz,1H), 7.60-7.65 (dt, J=1.2 and 6.9 Hz, 1H), 7.72-7.82 (m, 2H), 7.99-8.04(t, J=8.0 Hz, 2H), 8.41-8.44 (d, J=8.5 Hz, 1H), 10.99 (s, H); ¹³C NMR(DMSO-d₆) δ 22.37, 31.17, 45.12, 51.60, 71.05, 115.05, 115.52, 119.44,126.64, 127.20, 127.93, 128.51, 129.87, 129.91, 130.03, 133.40, 137.11,146.89, 153.29, 157.09, 167.94, 170.97, 172.83; Calcd. For C₂₃H₁₉N₃O₄:C, 68.82; H, 4.77; N, 10.47; Found: C, 68.66; H, 4.49; N, 10.24.

5.1443-(1-OXO-4-(QUINOLIN-3-YLMETHOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A solution of 3-quinolinecarboxaldehyde (1.2 g, 7.6 mmol) inreagent alcohol (60 mL) was cooled in dry ice/acetone bath to −40° C.LiBH₄/THF (2 M, 4.6 mL, 9.2 mmol) was added dropwise at −40 to −60° C.The reaction mixture was stirred at −60° C. for 1 hour then quenchedwith water (10 mL). The mixture was concentrated and the residue wasdissolved in EtOAc (90 mL). EtOAc solution was washed with saturatedNaHCO₃ (30 mL) and brine (30 mL) and dried. The solvent was removed togive quinolin-3-ylmethanol (1.2 g, 100%).

Step 2: Diisopropyl azodicarboxylate (1.6 g, 7.7 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopenatnoate (1.1 g, 3.8mmol), quinolin-3-ylmethanol (1.2 g, 7.9 mmol) andtriphenylphosphine-polymer bound (2.6 g, 7.7 mmol) in THF (80 mL) at5-8° C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and solid was washed withmethylene chloride (25 mL). Filtrate was concentrated and the residuewas purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to givemethyl5-amino-5-oxo-4-(1-oxo-4-(quinolin-3-ylmethoxy)isoindolin-2-yl)pentanoate(1.0 g, 24%).

Step 3: Potassium t-butoxide (0.3 g, 2.4 mmol) was added to a stirredsolution of methyl5-amino-5-oxo-4-(1-oxo-4-(quinolin-3-ylmethoxy)isoindolin-2-yl)pentanoate(1.0 g, 2.4 mmol) in THF (50 mL) at 5° C. The reaction mixture wasstirred at 5° C. for 10 minutes then warmed to room temperature for 2hours. The reaction mixture was cooled in an ice bath and quenched with4N HCl (4 mL). The mixture was diluted with methylene chloride (80 mL)and washed with saturated NaHCO₃ (30 mL) and water (40 mL) and dried.The solvent was removed and solid was slurried with hot methanol (10 mL)to give3-(1-oxo-4-(quinolin-3-ylmethoxy)isoindolin-2-yl)piperidine-2,6-dione(0.1 g, 47%) as a white solid: mp 270-273° C.; ¹H NMIR (DMSO-d6) δ1.99-2.01 (m, 1H), 2.43-2.60 (m, 2H), 2.91 (m, 1H), 4.33 (d, J=17.4 Hz,1H), 4.40 (d, J=17.7 Hz, 1H), 5.09-5.15 (dd, J=5.1 and 13.2 Hz, 1H),5.49 (s, 2H), 7.37 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.52 (t,J=7.8 Hz, 1H), 7.64 (dt, J=1.0 and 8.0 Hz, 1H), 7.79 (dt, J=1.5 and 6.9Hz, 1H), 8.03 (t, J=8.5 Hz, 2H), 8.48 (d, J=1.3 Hz, 1H), 9.04 (d, J=2.1Hz, 1H), 10.98 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 45.08, 51.57,67.52, 115.07, 115.51, 126.94, 127.24, 128.09, 128.72, 129.68, 129.72,129.87, 130.06, 133.38, 134.68, 147.22, 150.52, 153.28, 167.95, 170.94,172.81; Calcd for C₂₃H₁₉N₃O₄+0.2H₂O: C, 68.21; H, 4.83; N, 10.37. Found:C, 68.29; H, 4.87; N, 10.15.

5.1453-[4-(CHROMAN-3-YLMETHOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer bonded triphenylphosphine (1.6 g, 2.04 mmol, 1.25mmol/g) was added to the stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (300 mg, 1.02 mmol) in THF (10 mL) at 0° C. The resultingmixture was stirred at 0° C. for 10 minutes, followed by the addition ofDIAD (412 mg, 2.04 mmol). Ten minutes later, chroman-3-yl-methanol (336mg, 2.04 mmol) was added to the mixture. The reaction was stirred atroom temperature for 16 hours and the reaction was complete. Thereaction mixture was filtered and the solid was washed withdichloromethane (5×20 mL). The filtrate was concentrated and the residuewas purified by ISCO chromatography to give4-carbamoyl-4-[4-(chroman-3-ylmethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a yellow glass like solid (400 mg, 90% yield): LCMSMH=439.

Step 2: KOtBu (102.4 mg, 0.91 mmol) was added to the stirred solution of4-carbamoyl-4-[4-(chroman-3-ylmethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (400 mg, 0.91 mmol) in tetrahydrofuran (20 mL) at 0°C. The mixture was stirred at room temperature for 5 hours, followed bythe addition of HCl (aq. 1N, 1.3 mL) and then water (10 mL). The mixturewas extracted with dichloromethane (2×25 mL). Organic layers were driedby MgSO₄ and concentrated under vacuo. The residue was purified by ISCOchromatography and prep HPLC to give3-[4-(Chroman-3-ylmethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (30 mg, 7.9% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 (acetonitrile/0.1% H₃PO₄):t_(R)=7.07 (100%); mp: 258-260° C.; ¹H NMR (DMSO-d₆) δ 1.92-2.08 (m, 1H,CHH), 2.34-2.45 (m, 1H, CHH), 2.54-2.65 (m, 2H, CH₂), 2.66-2.81 (m, 1H,CHH), 2.82-3.02 (m, 2H, CH₂), 3.97-4.48 (m, 6H, CH₂, CH₂, CH₂),5.04-5.19 (m, 1H, CHN), 6.70-6.89 (m, 2H, Ar), 7.01-7.15 (m, 2H, Ar),7.29 (dd, J=7.7, 18.1 Hz, 2H, Ar), 7.42-7.52 (m, 1H, Ar), 10.99 (s, 1H,NH). *one proton is overlapped with DMSO, which was proved by HMQC; ¹³CNMR (DMSO-d₆) δ 22.37, 26.66, 31.15, 31.72, 31.75, 44.89, 51.52, 66.88,68.18, 114.48, 115.18, 116.14, 120.26, 121.02, 127.07, 129.86, 129.99,133.20, 153.52, 154.11, 167.99, 170.97, 172.83; LCMS MH=407.

5.1463-[4-(4-BENZOTRIAZOL-1-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To a solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.683 g, 1.43 mmol) in acetonitrile (10 ml) was added1H-benzo[d][1,2,3]triazole (0.205 g, 1.72 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.285 ml, 1.724 mmol). The mixturewas stirred overnight and then concentrated to give crude methyl4-(4-(4-(4-((H-benzo[d][1,2,3]triazol-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoateas a white foamy solid (1.30 g). It was used in the next step withoutfurther purification.

Step 2: To a stirred white suspension of methyl4-(4-(4-((1H-benzo[d][1,2,3]triazol-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(0.73 g, 1.43 mmol) in THF (12 ml) in an ice bath was added potassium2-methylpropan-2-olate (0.46 g, 4.11 mmol). The mixture was stirred for15 minutes and was quenched with 1 N HCl (˜3 ml) and then neutralized bysaturated sodium bicarbonate (6 ml to pH=7). The mixture was stirredwith ethyl acetate (20 ml), and then filtered to give a white solid. Itwas purified on silica gel column (MeOH/CH₂Cl₂ gradient from 1% to 5% in30 min) to give3-[4-(4-benzotriazol-1-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white powder (340 mg, 49% yield); mp, 228-230° C.; HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 6.44min (98.2%); ¹H NMR (DMSO-d₆) δ 1.89-2.03 (m, 1H, CH), 2.33-2.47 (m, 1H,CH), 2.52-2.62 (m, 1H, CH), 2.81-2.98 (m, 1H, CH), 4.14-4.45 (m, 2H,CH₂), 5.09 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.20 (s, 2H, CH₂), 6.00 (s,2H, CH₂), 7.26-7.58 (m, 11H, ArH), 7.86 (d, J=8.5 Hz, 1H, ArH), 8.06 (d,J=8.3 Hz, 1H, ArH), 10.95 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 31.20,45.06, 50.64, 51.55, 69.12, 110.65, 114.89, 115.27, 119.22, 124.04,127.45, 127.88, 128.15, 129.79, 129.94, 132.64, 133.31, 135.65, 136.53,145.31, 153.37, 167.98, 170.94, 172.82. LC/MS MH=482; Anal Calcd forC₂₇H₂₃N₅O₄+0.7H₂O: C, 65.63; H, 4.98; N, 14.17; Found: C, 65.39; H,4.79; N, 13.96.

5.147 3-(4-(2-CHLOROBENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a slurry of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (200 mg,0.684 mmol) and Cs₂CO₃ (233 mg, 0.677 mmol) in dry DMF (5 mL), was added1-chloro-2-chloromethyl-benzene (820 μl, 10% solution in DMF, 0.650mmol). The reaction mixture was stirred at room temperature and progresswas monitored by LCMS. After 2 hours, N,N-diisopropylethylamine (120 μL,0.684 mmol) was added, and the mixture was stirred at room temperatureovernight. After 14 hours, the mixture was warmed up in oil bath to 80°C. and stirred for 8 hours. The crude reaction mixture was cooled on anice bath and then transferred in small portions to a cooled 0.5N aqueousHCl solution (40 mL). A white solid formed was collected by filtration,washed with additional water on filter funnel, and dried in vacuum ovento give 220 mg of crude product. The solid was dissolved in minimal DMFand purified by injection onto a C-18 preparatory HPLC column. Theproduct was eluted with an acetonitrile/water gradient (0.1% formic acidin both mobile phases, 30% to 75% acetonitrile over 20 min) andfractions were collected by mass trigger. The desired fractions werecombined and concentrated in vacuo to give3-(4-(2-chlorobenzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as awhite solid (175 mg, 70% yield): HPLC: Waters Symmetry C18, 5 m, 3.9×150mm, 1 ml/min, 240 nm, 50/50 acetonitrile/0.1% H3PO4, 4.08 min (98.7%);mp: 213-215° C.; 1H NMR (DMSO-d6) δ 1.87-2.05 (m, 1H, CHH), 2.32-2.48(m, 1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.82-3.00 (m, 1H, CHH), 4.26 (d,J=17.6 Hz, 1H, CHH), 4.46 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.1Hz, 1H, CH), 5.31 (s, 2H, CH2), 7.27-7.46 (m, 4H, Ar), 7.48-7.59 (m, 2H,Ar), 7.62-7.72 (m, 1H, Ar), 10.96 (s, 1H, NH); 13C NMR (DMSO-d6) δ22.30, 31.16, 45.03, 51.55, 67.25, 114.93, 115.51, 127.38, 129.42,129.90, 129.95, 130.03, 130.22, 132.72, 133.37, 133.85, 153.26, 167.91,170.96, 172.80; LCMS MH=385, 387; Anal. Calcd. For C₂₀H₁₇ClN₂O₄+0.35H₂O:C, 61.42; H, 4.56; N, 7.16; Cl, 9.06; Found: C, 61.26; H, 4.32; N, 7.19;Cl, 9.18.

5.1483-(1-OXO-4-(2,4,6-TRICHLOROBENZYLOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A solution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.50 g, 1.7mmol) and 2,4,6-trichlorobenzyl alcohol (0.72 g, 3.4 mmol) in THF (30mL) was cooled to 0° C. Polymer bound triphenyl phosphine (3 mmol/gloading, 1.2 g, 3.7 mmol) was added, followed by DIAD (0.76 μm 3.7mmol). After one hour, the cooling bath was removed, and the mixturestirred under nitrogen for 20 hours. The mixture was filtered, and thefilter was rinsed with ethyl acetate (50 mL). The filtrate was dilutedwith additional ethyl acetate (50 mL) and washed with brine (3×100 mL)and evaporated. The residue was chromatographed in a methylenechloride-methanol gradient, eluting the product at 5% methanol. Crudemethyl5-amino-5-oxo-4-(1-oxo-4-(2,4,6-trichlorobenzyloxy)isoindolin-2-yl)pentanoate(1.15 g (>100%)) was obtained as a glue.

Step 2: The crude material obtained in Step 1 was dissolved in THF (25mL) and cooled to 0° C. Then, potassium tert-butoxide (0.19 g, 1.7 mmol)was added, and the mixture was stirred under nitrogen for 3 hours. Themixture was quenched by the addition of 5 drops acetic acid. Theresulting mixture was diluted with ethyl acetate (75 mL) and washed withsaturated aqueous sodium bicarbonate solution (75 mL) and evaporatedunder vacuum. The residue was chromatographed in a methylenechloride-methanol gradient, eluting the product at 5% methanol. Afterevaporation of the appropriate fractions, the residue was slurried inether (15 mL) for 1 hour, filtered, and dried under vacuum, providingthe product as a white solid, 0.53 g, in 68% yield over two steps; HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50(acetonitrile/0.1% H₃PO₄): t_(R)=6.94 (97.86%); mp 138-140° C.; ¹H NMR(DMSO-d₆) δ 1.88-2.02 (m, 1H, CHH), 2.33-2.47 (m, 1H, CHH), 2.53-2.62(m, 1H, CHH), 2.79-2.98 (m, 1H, CHH), 4.16 (d, J=17.6 Hz, 1H, CHH), 4.32(d, J=17.6 Hz, 1H, CHH), 5.09 (dd, J=5.0, 13.1 Hz, 1H, CH), 5.33 (d,J=10.6 Hz, 1H, CHH), 5.39 (d, J=10.8 Hz, 1H, CHH), 7.39 (d, J=7.2 Hz,1H, Ar), 7.45-7.61 (m, 2H, Ar), 7.81 (s, 2H, Ar), 10.94 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 22.26, 31.18, 44.99, 51.58, 65.00, 115.07, 115.89,128.58, 129.90, 130.03, 130.62, 133.44, 135.09, 136.85, 153.40, 167.83,170.95, 172.79; LCMS MH=453/455/457; Anal. Calcd for C₂₀H₁₅Cl₃N₂O₄.0.4Et₂O: C, 53.67; H, 3.96; N, 5.80; Found: C, 53.65; H, 3.89; N, 5.71.

5.1493-[4-(2,5-DICHLORO-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the solution of3-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.5g, 1.7 mmol) in THF (30 mL), was added triphenyl phosphine (polymersupported 2.2 mmol/g, 1.64 g, 3.74 mmol). The mixture was stirred atroom temperature for 15 minutes. Diisopropyl azodicarboxylate (0.76 mL,3.74 mmol) was added at 0° C. and the mixture was stirred at 0° C. for30 minutes. 2,5-Dichloro phenylmethanol (0.45 g, 2.57 mmol) was added at0° C., and the mixture was allowed to warm to room temperature andstirred at room temperature overnight. The reaction mixture was filteredand the filtrate was concentrated. The resulting oil was purified onsilica gel column eluted with methylene chloride and methanol (gradient,product came out at 6% methanol) to give4-carbamoyl-4-[4-(2,5-dichloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.7 g, 92%).

Step 2: To the THF solution (30 mL) of4-carbamoyl-4-[4-(2,5-dichloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.7 g, 1.5 mmol) was added potassium tert-butoxide(0.17 g, 1.7 mmol) at 0° C. The mixture was stirred at 0° C. for 10minutes and was quenched with 1N HCl (5 mL, 5 mmol), followed bysaturated NaHCO₃ (25 mL). The mixture was extracted with EtOAc (50mL×2). The organic layer was washed with water (30 mL) and brine (30mL), dried over MgSO₄, and concentrated. To the resulting solid wasadded EtOAc (10 mL) followed by hexane (10 mL) under stirring. Thesuspension was filtered to give3-[4-(2,5-Dichloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas white solid (0.26 g, 37%). mp: 256-258° C.; HPLC: Waters SymmetryC₁₈, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, gradient to 95/5acetonitrile/0.1% H₃PO₄ in 5 min: t_(R)=6.87 min (96.5%); ¹H NMR(DMSO-d₆) δ 1.67-2.16 (m, 1H, CHH), 2.36-2.46 (m, J=4.2 Hz, 1H, CHH),2.53-2.65 (m, J=19.5 Hz, 1H, CHH), 2.76-3.09 (m, 1H, CHH), 4.13-4.60 (m,2H, CH₂), 5.11 (dd, J=5.0, 13.1 Hz, 1H, NCH), 5.29 (s, 2H, CH₂),7.34-7.43 (m, 2H, Ar), 7.46-7.63 (m, 3H, Ar), 7.73 (d, J=2.5 Hz, 1H,Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.27, 31.14, 345.02, 51.56,66.75, 114.95, 115.68, 129.66, 129.78, 129.88, 129.94, 131.11, 131.37,131.91, 133.41, 136.01, 153.05, 167.83, 170.91, 172.76; LCMS: 465; AnalCalcd for C₂₆H₁₆C₁₂N₂O₄+0.2H₂O: C, 56.81; H, 3.91; N, 6.62; Found: C,56.75; H, 4.19; N, 6.70.

5.1503-[4-(3-METHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer-supported triphenylphosphene (1.6 mmol/g, 2.40 g, 3.80mmol) was added to a stirred solution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.50 g, 1.71mmol) in THF (10 mL) at 0° C., followed by addition of diisopropyldiazene-1,2-dicarboxylate (0.75 ml, 3.80 mmol). After stirring for 30minutes, (2,3-dichloro-phenyl)-methanol (0.45 g, 2.60 mmol) was added.The mixture was stirred for one hour then filtered, washed with methanol(3×10 mL), methylene chloride (3×10 mL). The combined filtrate wasevaporated in vacuo to give an oil, which was purified on silica gelcolumn (EtOAc/Hexanes gradient from 20% to 100% in 90 min) to give4-carbamoyl-4-[4-(2,3-dichloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a white solid (0.35 g, 45% yield).

Step 2: Potassium tert-butoxide (0.17 g, 1.50 mmol) was added to astirred suspension of4-carbamoyl-4-[4-(2,3-dichloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.34 g, 0.75 mmol) in THF (20 mL) at 0° C. Themixture was stirred for ten minutes and quenched with 1N HCl (3 mL),neutralized by saturated sodium bicarbonate (4 mL to pH=7), and quicklyextracted by ethyl acetate (2×30 mL). The combined ethyl acetate phaseswere evaporated and purified on silica gel column (MeOH/CH₂Cl₂, gradientfrom 1% to 9% in 60 min) to give3-[4-(2,3-dichloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (0.03 g, 9% yield); HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, isocratic at 50/50 in 10 min (CH₃CN/0.1%H₃PO₄), 5.84 min (96.1%); mp: 272-274° C.; ¹H NMR (DMSO-d₆) δ 1.90-2.05(m, 1H, CHH), 2.37-2.47 (m, H, CHH), 2.53-2.65 (m, 1H, CHH), 2.83-3.01(m, 1H, CHH), 4.22-4.50 (m, 2H, CH₂), 5.12 (dd, J=5.2, 13.1 Hz, 1H,NCH), 5.35 (s, 2H, CH₂), 7.32-7.73 (m, 6H, Ar), 10.97 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 22.35, 31.20, 45.05, 51.59, 67.56, 114.97, 115.68,128.41, 128.51, 129.95, 130.30, 130.60, 131.98, 133.44, 136.57, 153.09,167.90, 170.96, 172.83; LCMS MH=419, 421; Anal Calcd for C₂₀H₁₆N₂O₄Cl₂:C, 57.30; H, 3.85; N, 6.68; Cl, 16.91; Found: C, 57.31; H, 3.86; N,6.46; Cl, 17.02.

5.1513-(4-(3,4-DIMETHOXYBENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Diisopropyl azodicarboxylate (1.3 g, 6.1 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.9 g, 3.1mmol), 3,4-dimethoxybenzyl alcohol (0.8 g, 4.6 mmol) andtriphenylphosphine-polymer bound (2.1 g, 6.2 mmol) in THF (80 mL) at5-8° C. After addition, the mixture was stirred at room temperatureovernight. The reaction mixture was filtered and solid was washed withmethylene chloride (30 mL). The filtrate was concentrated and theresidue was purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) togive methyl5-amino-4-(4-(3,4-dimethoxybenzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 3.8%).

Step 2: A solution of potassium t-butoxide in THF (I M, 1.2 mL, 1.2mmol), was added to a stirred solution of methyl5-amino-4-(4-(3,4-dimethoxybenzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 1.2 mmol) in THF (30 mL) at 5° C. The mixture was stirred at 5°C. for 10 minutes then warmed to room temperature for 2 hours. Thereaction mixture was cooled in an ice bath and quenched with 4N HCl (4mL). The mixture was diluted with methylene chloride (70 mL) and water(20 mL). The organic layer was washed with brine (40 mL) and dried. Thesolvent was removed and the residue was purified by chromatography(SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give3-(4-(3,4-dimethoxybenzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.2 g, 32%) as a white solid: mp 205-207° C.; ¹H NMR (DMSO-d₆) δ1.96-2.00 (m, 1H), 2.41-2.60 (m, 2H), 2.91 (m, 1H), 3.76 (s, 6H), 4.26(d, J=17.7 Hz, 1H), 4.37 (d, J=17.4 Hz, 1H), 5.07-5.13 (m, 3H),6.94-7.09 (m, 3H), 7.31-7.35 (m, 2H), 7.48 (t, J=7.8 Hz, 1H), 10.96 (s,1H); 13C NMR (DMSO-d₆) δ 22.30, 31.17; 45.11, 51.56, 55.47, 69.67,111.59, 111.90, 115.07, 115.12, 120.51, 128.80, 129.75, 129.96, 133.24,148.65, 153.51, 168.00, 170.96, 172.82; Calcd. For C₂₂H₂₂N₂O₆: C, 64.38;H, 5.40; N, 6.83; Found: C, 64.36; H, 5.25; N, 6.85.

5.1523-[4-(3-CHLORO-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the THF solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (1.0 g, 3.42 mmol), was added triphenyl phosphine resin(2.3 g, 2.2 mmol/g loading, 6.84 mmol) and DIAD (1.33 mL, 6.84 mmol) at0° C. After being stirred at 0° C. for 10 minutes, the mixture was added(3-chloro-4-ylmethyl-phenyl)-methanol (0.61 mL, 5.13 mmol) and stirredat room temperature overnight. The mixture was filtered and the filtratewas concentrated and extracted with EtOAc (30 mL) and Na₂CO₃ (20 mL).The organic layer was washed with water (20 mL) and brine (20 mL), andconcentrated. The resulting oil was purified on silica gel column togive4-carbamoyl-4-[4-(3-chloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as an oil (0.24 g, 20%).

Step 2: To the THF solution (20 mL) of4-carbamoyl-4-[4-(3-chloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.24 g, 0.57 mmol), was added potassium t-butoxide(0.57 mL g, 0.57 mmol) at 0° C. The mixture was stirred for 15 minutesat 0° C. and quenched with 5 mL of 1N HCl solution followed by 15 mL ofsaturated NaHCO₃ solution. The mixture was extracted with EtOAc (20 mL).The organic layer was concentrated in vacuo. The resulting oil waspurified on silica gel column eluted with CH₂Cl₂ and methanol to give3-[4-(4-Chloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (60 mg, 27%). mp: 224-226° C. HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1%H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R)=4.9 min (97%). ¹H NMR (DMSO-d₆) δ 1.88-2.05 (m, J=1.9 Hz, 1H,CHH), 2.34-2.46 (m, 1H, CHH), 2.57-2.65 (m, J=3.6 Hz, 1H, CHH),2.79-3.02 (m, 1H, CHH), 4.16-4.61 (m, 2H, CH₂), 5.11 (dd, J=5.2, 13.1Hz, 1H, NCH), 5.27 (s, 2H, CH₂), 7.19-7.38 (m, 2H, Ar), 7.38-7.54 (m,4H, Ar), 7.56 (s, 1H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.36,31.21, 45.09, 51.61, 68.59, 114.95, 115.43, 126.19, 127.33, 127.91,129.84, 129.98, 130.42, 133.13, 133.39, 139.20, 153.24, 167.95, 170.99,172.87; LCMS MH=385. Anal Calcd for C₂₀H₁₇N₂O₄Cl: C, 62.42; H, 4.45; N,7.28; Found: C, 61.51% H, 4.04; N, 7.12.

5.153 3-(4-(3-(2-(DIMETHYLAMINO)ETHOXY)-4-METHOXYBENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A mixture of 3-hydroxy-4-methoxybenzaldehyde (4.2 g, 27.3 mmol)and Cs₂CO₃ (22.2 g, 68.2 mmol) in DMF (80 mL) was stirred for 10minutes. To this mixture was added dimethylaminoethyl chloridehydrochloride (4.7 g, 32.7 mmol). The reaction mixture was stirred at50° C. oil bath for 18 hours. The reaction mixture was cooled andfiltered. Filtrate was diluted with water (200 mL) and extracted withEtOAc (4×50 mL). Combined EtOAc solution was washed with water (3×50 mL)and brine (50 mL), and dried. The solvent was removed to give3-(2-(dimethylamino)ethoxy)-4-methoxybenzaldehyde (3.8 g, 62%).

Step 2: A solution of 3-(2-(dimethylamino)ethoxy)-4-methoxybenzaldehyde(3.8 g, 16.8 mmol) in THF (20 mL) was added to a stirred solution ofLiBH₄/THF (2.0M, 10.1 mL) in THF (20 mL) at 6-10° C. After addition, themixture was stirred at room temperature for 1 hour. The reaction mixturewas cooled in an ice bath and quenched with water (15 mL). The mixturewas extracted with EtOAc (3×50 mL) and combined EtOAc solution waswashed with water (40 mL) and brine (40 mL), and dried. The solvent wasremoved and the residue was purified by chromatography (SiO₂, EtOAc:CH₂C₂ 3: 7) to give 3-(2-(dimethylamino)ethoxy-4-methoxyphenyl)methanol(3.6 g, 94% yield): ¹H NMR (DMSO-d₆) δ 2.62 (s, 6H). 3.13 (t, J=5.4 Hz,2H), 3.73 (s, 3H), 4.31 (t, J=5.4 Hz, 2H), 4.42 (d, J=5.7 Hz, 2H), 5.08(t, J=5.7 Hz, 1H), 6.84-6.97 (m, 3H); ¹³C NMR (DMSO-d₆) δ 51.74, 55.70,61.89, 62.63, 64.07, 111.91, 112.38, 119.38, 135.12, 147.15, 147.97.

Step 3: Diisopropyl azodicarboxylate (0.9 g, 4.4 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.7 g, 2.2mmol), 3-(2-(dimethylamino)ethoxy-4-methoxyphenyl)methanol (0.8 g, 3.3mmol) and triphenylphosphine-polymer bound (1.5 g, 4.4 mmol) in THF (80mL) at 5-8° C. After addition, the mixture was stirred at roomtemperature overnight. The reaction mixture was filtered and solid waswashed with methylene chloride (30 mL). Filtrate was concentrated, andthe residue was purified by chromatography (SiO₂, CH₃OH:CH₂Cl₂ 3:97) togive methyl5-amino-4-(4-(3-(2-(dimethylamino)ethoxy)-4-methoxybenzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.6 g, 54%).

Step 4: Potassium t-butoxide/THF (1M, 1.3 mL, 1.3 mmol) was added to astirred solution of methyl5-amino-4-(4-(3-(2-(dimethylamino)ethoxy)-4-methoxybenzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.6 g, 1.3 mmol) in THF (20 mL) at 5° C. The mixture was stirred at 5°C. for 10 minutes then warmed to room temperature for 2 hours. Thereaction mixture was cooled in an ice bath and quenched with saturatedNH₄Cl (6 mL). The mixture was diluted with methylene chloride (70 mL)and saturated NaHCO₃ (20 mL). The organic layer was washed with water(40 mL) and brine (40 mL), and dried. The solvent was removed and theresidue was purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) togive3-(4-(3-(2-(dimethylamino)ethoxy)-4-methoxybenzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.2 g, 39%) as a white solid: mp 201-203° C.; ¹H NMR (DMSO-d6) δ1.95-2.00 (m, 1H), 2.40-2.52 (m, 2H), 2.61 (s, 6H), 2.84-2.95 (m, 1H),3.11-3.17 (m, 2H), 3.76 (s. 3H), 4.26 (d, J=17.7 Hz, 1H), 4.34 (t, J=5.4Hz, 2H), 4.37 (d, J=17.7 Hz, 1H), 5.07-5.13 (dd, J=5.1 and 13.2 Hz, 1H),5.15 (s, 2H), 7.00 (d, J=8.4 Hz, 1H), 7.05-7.08 (dd, J=1.8 and 8.1 Hz,1H), 7.16 (d, J=1.8 Hz, 1H), 7.31-7.35 (m, 2H), 7.48 (t, J=7.8 Hz, 1H),10.96 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 45.09, 51.54, 51.73,55.67, 61.76, 64.10, 69.55, 112.01, 113.75, 115.09, 115.16, 121.31,128.89, 129.77, 129.96, 133.25, 147.25, 149.00, 153.50, 168.00, 170.95,172.80; Calcd. For C₂₅H₂₉N₃O₆+0.1H₂O: C, 61.84; H, 6.44; N, 8.65; Found:C, 62.02; H, 6.67; N, 8.58.

5.154 3-(4-(4-(2-(DIMETHYLAMINO)ETHOXY)-3-METHOXYBENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A mixture of vanillin (2 g. 27.3 mmol) and Cs₂CO₃ (22.2 g, 68.2mmol) in DMF (80 mL) was stirred for 10 minutes. To this mixture wasadded diemthylaminoethyl chloride (4.7 g, 32.7 mmol). The mixture wasstirred at 50° C. oil bath for 18 hours. The reaction mixture wasfiltered. Filtrate was diluted with water (100 mL) and extracted withEtOAc (4×50 mL). EtOAc solution was washed with water (3×50 mL) andbrine (50 mL), and dried. The solvent was removed to give4-(2-(dimethylamino)ethoxy)-3-methoxybenzaldehyde (2.1 g, 34%).

Step 2: A solution of 4-(2-(dimethylamino)ethoxy)-3-methoxybenzaldehyde(1.8 g, 8.1 mmol) in THF (15 mL) was added to a stirred solution ofLiBH₄/THF (2M, 4.8 mL, 9.7 mmol) in THF (15 mL) at 8 to 10° C. Afteraddition, reaction mixture was stirred at room temperature for 1 hour.The reaction mixture was cooled in an ice bath and quenched with water(10 mL). The mixture was stirred with saturated NaHCO₃ (25 mL) and EtOAc(50 mL). The aqueous layer was extracted with EtOAc (2×30 mL). CombinedEtOAc solution was washed with brine (40 mL) and dried. The solvent wasremoved and the residue was purified by chromatography (SiO₂, EtOAc:CH₂Cl₂ 3: 7) to give(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl)methanol (2.6 g, 93%yield): ¹H NMR (DMSO-d₆) δ 2.61 (s, 6H), 3.11 (t, J=5.4 Hz, 2H), 3.75(s, 3H), 4.30 (t, J=5.4 Hz, 2H), 4.41 (d, J=5.7 Hz, 2H), 5.09 (t, J=5.7Hz, 1H), 6.81-6.96 (m, 3H); ¹³C NMR (DMSO-d₆) δ 51.69, 55.48, 61.85,62.69, 64.29, 110.81, 113.61, 118.51, 136.02, 146.11, 149.01.

Step 3: Diisopropyl azodicarboxylate (1.4 g, 6.8 mmol) was added to astirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopenatnoate (1.0 g, 3.4mmol), (4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl)methanol (1.2 g, 5.1mmol) and triphenphosphine-polymer bound (2.3 g, 6.8 mmol) in THF (80mL) at 5-8° C. After addition, the mixture was stirred at roomtemperature overnight. The reaction mixture was filtered and solid waswashed with methylene chloride (30 mL). Filtrate was concentrated andthe residue was purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97)to give methyl5-amino-4-(4-(4-(2-dimethylamino)ethoxy)-3-methoxybenzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.4 g, 8.1%).

Step 4: A solution of potassium t-butoxide/THF (1M, 3.0 mL, 3.0 mmol)was added to a stirred solution of methyl5-amino-4-(4-(4-(2-(dimethylamino)ethoxy)-3-methoxybenzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.5 g, 3.0 mmol) in THF (30mL) at 5° C. The mixture was stirred at 5° C. for 10 minutes then warmedto room temperature for 2 hours. The reaction mixture was cooled in anice bath and quenched with saturated NH₄Cl (10 mL). The mixture wasdiluted with CH₂Cl₂ (50 mL) and saturated NaHCO₃ (25 mL). The aqueouslayer was extracted with CH₂Cl₂ (2×30 mL) and combined CH₂Cl₂ solutionwas washed with brine (40 mL) and dried. The solvent was removed and theresidue was purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) togive3-(4-(4-(2-(dimethylamino)ethoxy)-3-methoxybenzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.6 g, 39%) as a white solid: mp 190-192° C.; ¹H NMR (DMSO-d₆) δ1.95-2.00 (m, 1H), 2.41-2.55 (m, 2H), 2.61 (s, 6H), 2.84-2.91 (m, 1H),3.13 (t, J=5.4 Hz, 2H), 3.77 (s, 3H), 4.27 (d, J=17.5 Hz, 1H), 4.33 (t,J=5.4 Hz, 2H), 4.37 (d, J=17.5 Hz, 1H), 5.07-5.13 (dd, J=5.1 and 13.2Hz, 1H), 5.16 (s, 2H), 7.02 (m, 2H), 7.12 (b, 1H), 7.31-7.35 (m, 2H),7.48 (t, J=7.8 Hz, 1H), 10.96 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.31, 31.17,45.11, 51.56, 51.72, 55.67, 61.77, 64.14, 69.59, 112.24, 113.42, 115.05,115.16, 120.50, 129.77, 129.95, 133.25, 147.22, 149.06, 153.50, 168.00,170.96, 172.82; Calcd. For C₂₅H₂₉N₃O₆+1.0H₂O: C, 61.34; H, 6.44; N,8.65; Found: C, 61.98; H, 6.84; N, 8.67.

5.1553-[4-(4-CHLORO-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the THF solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (1.0 g, 3.42 mmol), were added triphenyl phosphine resin(2.3 g, 2.2 mmol/g loading, 6.84 mmol) and DIAD (1.33 mL, 6.84 mmol) at0° C. After being stirred at 0° C. for 10 minutes, the mixture was added(4-chloro-4-ylmethyl-phenyl)-methanol (0.73 g, 5.13 mmol) and stirred atroom temperature overnight. The mixture was filtered and the filtratewas concentrated and extracted with EtOAc (30 mL) and Na₂CO₃ (20 mL).The organic layer was washed with water (20 mL) and brine (20 mL), andconcentrated. The resulting oil was purified on silica gel column togive4-carbamoyl-4-[4-(4-chloro-benzyloxy)-1-oxo-1,3-dihydroisoindol-2-yl]-butyricacid methyl ester (0.13 g, 13%).

Step 2: To the THF solution (20 mL) of4-carbamoyl-4-[4-(3-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.18 g, 0.43 mmol), was added potassium t-butoxide(0.6 mL g, 0.6 mmol) at 0° C. The mixture was stirred for 15 minutes at0° C. and quenched with 5 mL of 1N HCl solution, followed by 15 mL ofsaturated NaHCO₃ solution. The mixture was extracted with EtOAc (20 mL).The organic layer was concentrated in vacuo. The resulting oil waspurified on silica gel column eluted with CH₂Cl₂ and methanol to give3-[4-(4-chloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (70 mg, 42%). mp: 238-240° C. HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1%H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R)=3.9 min (97%). ¹H NMR (DMSO-d₆) δ 1.81-2.08 (m, 1H, CHH),2.34-2.48 (m, 1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.80-3.01 (m, 1H, CHH),4.15-4.51 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.26 (s, 2H,CH₂), 7.13-7.39 (m, 2H, Ar), 7.41-7.58 (m, 5H, Ar), 10.97 (s, 1H, NH).¹³C NMR (DMSO-d₆) δ 22.38, 31.20, 45.06, 51.58, 68.65, 115.00, 115.38,128.47, 129.47, 129.82, 129.97, 132.55, 133.35, 135.70, 153.27, 167.96,170.98, 172.83; LCMS MH=385. Anal Calcd for C₂₀H₁₇ClN₂O₄+0.1H₂O: C,62.13; H, 4.48; N, 7.25; Found: C, 61.76% H, 4.45; N, 7.28.

5.1563-[4-(3-METHOXY-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer-supported triphenylphosphene (1.6 mmol/g, 3.84 g, 4.78mmol) was added to a stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.78 g, 2.66 mmol) in THF (15 mL) at 0° C., followed byaddition of diisopropyl diazene-1,2-dicarboxylate (0.95 ml, 4.78 mmol).After stirring for 30 minutes, (3-methoxy-phenyl)-methanol (0.56 mL,4.52 mmol) was added. The mixture was stirred for one hour thenfiltered, washed with methanol (3×10 mL), then methylene chloride (3×10mL). The combined filtrate was evaporated in vacuo to give an oil, whichwas purified on silica gel column (MeOH/CH₂Cl₂ gradient from 0% to 5% in60 min) to give4-carbamoyl-4-[4-(3-methoxy-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as an oil (0.32 g, 36% yield).

Step 2: Potassium tert-butoxide (0.10 g, 0.92 mmol) was added to astirred solution of4-carbamoyl-4-[4-(3-methoxy-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (1.13 g, 2.60 mmol) in THF (10 mL) at 0° C. for 10minutes. The mixture was quenched with 1N HCl (2 mL) and neutralizedwith saturated sodium bicarbonate (4 ml to pH=8). The mixture wasextracted with ethyl acetate (3×20 mL). The combined ethyl acetatephases were evaporated and then purified on silica gel column(MeOH/CH₂Cl₂ gradient from 0% to 5% in 40 min) to give3-[4-(3-methoxy-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (0.23 g, 65% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 40/60 in 10 min(acetonitrile/0.1% H₃PO₄), 5.32 min (98.9%); mp: 225-227° C.; ¹H NMR(DMSO-d₆) δ 1.88-2.09 (m, 1H, CHH), 2.37-2.47 (m, 1H, CHH), 2.53-2.65(m, 1H, CHH), 2.82-3.00 (m, 1H, CHH), 3.76 (s, 3H, CH₃), 4.20-4.52 (m,2H, ArCH₂N), 5.11 (dd, J=5.0, 13.1 Hz, 1H, NCH), 5.23 (s, 2H, ArC H₂O),6.91 (dd, J=1.7, 8.1 Hz, 1H, Ar), 7.00-7.12 (m, 2H, Ar), 7.23-7.38 (m,3H, Ar), 7.43-7.55 (m, 1H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.35, 31.21, 45.12, 51.61, 55.05, 69.38, 113.26, 115.00, 115.26,119.68, 129.59, 129.79, 129.97, 133.32, 138.19, 153.41, 159.35, 167.99,170.98, 172.83 (missing one aromatic carbon due to overlapping,confirmed by HMQC); LCMS MH=381; Anal. Calcd for C₂₁H₂₀N₂O₅+0.1H₂O: C,65.99; H, 5.33; N, 7.33; Found: C, 65.71; H, 5.36; N, 7.25.

5.1573-[4-(3-METHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer-supported triphenylphosphene (1.6 mmol/g, 3.76 g, 4.68mmol) was added to a stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.75 g, 2.60 mmol) in THF (15 mL) at 0° C., followed byaddition of diisopropyl diazene-1,2-dicarboxylate (0.93 ml, 4.68 mmol).After stirring for 30 minutes, m-tolyl-methanol (0.53 mL, 4.40 mmol) wasadded. The mixture was stirred for one hour then filtered, washed withmethanol (3×10 mL), then methylene chloride (3×10 mL). The combinedfiltrate was evaporated in vacuo to give an oil, which was purified onsilica gel column (MeOH/CH₂Cl₂ gradient from 0% to 5% in 60 min) to give4-carbamoyl-4-[4-(3-methyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as an oil (1.13 g, 137% crude yield).

Step 2: Potassium tert-butoxide (0.30 g, 2.60 mmol) was added to astirred solution of4-carbamoyl-4-[4-(3-methyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (1.13 g, 2.60 mmol) in THF (10 mL) at 0° C. for 10minutes. The mixture was quenched with 1N HCl (2 mL) and neutralizedwith saturated sodium bicarbonate (4 ml to pH=8). The mixture wasextracted with ethyl acetate (3×20 mL). The combined ethyl acetatephases were evaporated and purified on silica gel column (MeOH/CH₂Cl₂gradient from 0% to 5% in 40 min) to give3-[4-(3-methyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (0.21 g, 29% yield over two steps); HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 40/60 in10 min (acetonitrile/0.1% H₃PO₄), 7.89 min (99.4%); mp: 244-246° C.; ¹HNMR (DMSO-d₆) δ 1.90-2.06 (m, 1H, CHH), 2.32 (s, 3H, CH₃), 2.36-2.47 (m,1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.81-3.00 (m, 1H, CHH), 4.19-4.49 (m,2H, ArCH₂N), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.21 (s, 2H, ArC H₂O),7.11-7.20 (m, 1H, Ar), 7.23-7.37 (m, 5H, Ar), 7.43-7.55 (m, 1H, Ar),10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) 20.99, 22.36, 31.21, 45.12, 51.59,69.61, 114.98, 115.23, 124.78, 128.25, 128.38, 128.61, 129.81, 129.94,133.32, 136.53, 137.64, 153.50, 168.01, 170.98, 172.83; LCMS MH=365;Anal. Calcd for C₂₁H₂₀N₂O₄+0.2H₂O: C, 68.54; H, 5.59; N, 7.61; Found: C,68.18; H, 5.49; N, 7.52.

5.1583-(4-(3-METHOXY-4-(2-PYRROLIDIN-1-YL)ETHOXY)-BENZYLOXY)-1-OXO-ISOINDOLIN-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of Vanillin (4.2 g, 27.3 mmol) and Cs₂CO₃ (22.2 g,68.3 mmol) in DMF (80 mL) was stirred for 10 minutes at roomtemperature. To this mixture was added 1-(2-chloroethyl)pyrrolidinehydrochloride (5.6 g, 32.7 mmol). The mixture was heated at 50° C.overnight. The reaction mixture was cooled and filtered and washed solidwith EtOAc (100 mL). Filtrate was diluted with water (200 mL) andaqueous layer was extracted with EtOAc (3×50 mL). Combined EtOAcsolution was washed with water (2×50 mL) and brine (50 mL), and dried.The solvent was removed to give3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde (6.2 g, 91% yield):¹H NMR (DMSO-d₆) δ 1.65-1.71 (m, 4H), 2.50-2.55 (m, 4H), 2.81 (t, J=6.0Hz, 2H), 4.17 (t, J=6.0 Hz, 2H), 7.20 (d, J=8.1 Hz, 1H), 7.40 (d, J=1.8Hz, 1H), 7.52-7.55 (dd, J=1.8 and 8.1 Hz, 1H), 9.84 (s, 1H).

Step 2: A solution of LiBH₄/THF (2.0M, 14.7 mL, 29.4 mmol) in THF (20mL) was cooled in an ice bath to 5° C. A solution of3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde (6.1 g, 24.5 mmol) inTHF (20 mL) was added slowly at 5-8° C. After addition, the mixture wasstirred at room temperature for 1 hour. The reaction mixture was cooledin an ice bath and quenched with water (15 mL). The mixture was stirredwith EtOAc (50 mL) and sat. NaHCO₃ (25 mL). The aqueous layer wasextracted with EtOAc (2×40 mL) and combined EtOAc solution was washedwith water (40 mL) and brine (40 mL), and dried (MgSO₄). The solvent wasremoved and the residue was purified by chromatography (SiO₂, EtOAc:CH₂Cl₂ 2: 8) to give[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-methanol (4.8 g, 77%yield): ¹H NMR (DMSO-d₆) δ 1.85-2.01 (m, 4H), 2.96-3.08 (m, 4H), 3.12(t, J=5.7 Hz, 2H), 3.74 (s, 3H), 4.34 (t, J=5.7 Hz, 2H), 4.41 (d, J=5.6Hz, 2H), 5,07 (t, J=5.7 Hz, 1H), 6.80-6.84 (dd, J=1.8 and 8.1 Hz, 1H),6.94 (d, J=8.1 Hz, 2H); ¹³C NMR (DMSO-d₆) δ 22.28, 55.48, 61.34, 62.58,62.70, 64.65, 110.78, 113.26, 118.52, 135.84, 146.23, 148.91.

Step 3: Diisopropyl azodicarboxylate (1.1 g, 5.5 mmol) was added slowlyto a stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.7mmol), [3-methoxy-4-(2-pyrrolidine-1-yl-ethoxy)-phenyl]-methanol (1.0 g,4.1 mmol) and triphenylphosphine-polymer bound (1.8 g, 5.5 mmol) in THF(60 mL) at 5-7° C. After addition, the mixture was stirred at roomtemperature overnight. The reaction mixture was filtered and solid waswashed with CH₂Cl₂ (30 mL). Filtrate was concentrated and the residuewas purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to givemethyl5-amino-4-(4-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.9 g, 59%).

Step 4: A solution of potassium t-butoxide/THF (1M, 1.6 mL, 1.6 mmol)was added slowly to a stirred solution of methyl5-amino-4-(4-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzoyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.8 g, 1.6 mmol) in THF (30 mL) at 5° C. The mixture was stirred at 5°C. for 10 minutes then warmed to room temperature for 2 hours. Thereaction mixture was cooled in an ice bath and quenched with 4N HCl (3mL). The mixture was stirred with CH₂Cl₂ (40 mL) and sat. NaHCO₃ (25mL). The aqueous layer was extracted with CH₂Cl₂ (40 mL) and combinedCH₂Cl₂ solution was washed with water (2×25 mL) and brine (25 mL), anddried (MgSO₄). The solvent was removed and the residue was purified bychromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give3-(4-(3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzyloxy)-1-oxoisoindolin-2-yl)-piperidine-2,6-dione(0.4 g, 49% yield): mp 160-162° C.; ¹H NMR (DMSO-d₆) δ 1.96-2.01 (m,5H), 2.42-2.59 (m, 2H), 2.95-3.16 (m, 7H), 3.76 (s, 3H), 4.27 (d, J=17.4Hz, 1H), 4.35-4.42 (m, 3H), 5.07-5.13 (dd, J=5.4 and 13.5 Hz, 1H), 5.16(s, 2H), 6.98-7.02 (m, 2H), 7.11 (d, J=1.2 Hz, 1H), 7.30-7.35 (m, 2H),7.48 (t, J=7.8 Hz, 1H), 10.96 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.27, 31.17,45.12, 51.56, 55.57, 55.67, 60.48, 61.38, 64.55, 69.62, 112.24, 113.14,115.05, 115.15, 120.54, 129.53, 129.77, 129.95, 133.25, 147.34, 149.00,153.52, 168.00, 170.96, 172.81; Calcd for C₂₇H₃₁N₃O₆+BH₃: C, 63.91; H,6.75; N, 8.28. Found: C, 63.90; H, 6.76; N, 8.17.

5.1593-[4-(3,5-DICHLORO-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer bonded triphenylphosphine (1.6 g, 1.92 mmol) added tothe stirred solution of 4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (300 mg, 1.03 mmol)in THF (10 mL) at 0° C. The resulting mixture was stirred at 0° C. for10 minutes, followed by the addition of DIAD (412 mg, 2.06 mmol). Tenminutes later, (3,5-dichloro-phenyl)-methanol (364.7 mg, 2.06 mmol) wasadded to the mixture. The reaction was stirred at room temperature for 1hour and the reaction was complete. The reaction mixture was filteredand the solid was washed with dichloromethane (5×25 mL). The filtratewas concentrated and the residue was purified by ISCO chromatography togive4-carbamoyl-4-[4-(3,5-dichloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a white solid (410 mg, 88% yield): LCMS MH=451,453.

Step 2: KOtBu (102 mg, 0.91 mmol) was added to the stirred solution of4-carbamoyl-4-[4-(3,5-dichloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (410 mg, 0.91 mmol) in THF (20 mL) at 0° C. Theresulting mixture was stirred at 0° C. for 5 minutes and the reactionwas complete. To the reaction mixture was added by HCl (0.1N aq, 14 mL),and the mixture was extracted with dichloromethane (25 mL×2). Theorganic layer was dried by MgSO₄ and concentrated under vacuo. Theresidue was purified by ISCO chromatography to give a solid. The solidwas triturated with diethyl ether (15 mL) to give3-[4-(3,5-Dichloro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (230 mg, 60% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 60/40 (acetonitrile/0.1% H₃PO₄):t_(R)=3.5 (98%); mp: 271-273° C.; ¹H NMR (DMSO-d₆) δ 1.92-2.07 (m, 1H,CHH), 2.37-2.47 (m, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.81-3.02 (m, 1H,CHH), 4.22-4.56 (m, 2H, CHH, CHH), 5.12 (dd, J=5.1, 13.0 Hz, 1H, NCH),5.27 (s, 2H, CH₂), 7.29 (d, J=7.9 Hz, 1H, Ar), 7.35 (d, J=7.2 Hz, 1H,Ar), 7.46-7.54 (m, 1H, Ar), 7.57 (d, 2H, Ar), 7.58-7.63 (m, 1H, Ar),10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 31.18, 45.09, 51.60,67.92, 114.88, 115.57, 126.15, 127.57, 129.83, 129.99, 133.43, 134.14,140.97, 153.03, 167.90, 170.95, 172.81; LCMS MH=419, 421; Anal. Calcdfor C₂₀H₁₆C₁₂N₂O₄+0.045 CH₂Cl₂+0.06 MeOH: C, 56.82; H, 3.87; N, 6.59;Cl, 17.43; Found: C, 56.58; H, 3.86; N, 6.52; Cl, 17.15.

5.1603-[4-(4-METHANESULFONYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer bonded triphenylphosphine (1.5 g, 1.92 mmol) was addedto the stirred solution of 4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (280 mg, 0.96 mmol)in THF (10 mL) at 0° C. The resulting mixture was stirred at 0° C. for15 minutes, followed by the addition of DIAD (388 mg, 1.92 mmol). Fiveminutes later, (4-methanesulfonyl-phenyl)-methanol (357 mg, 1.92 mmol)was added to above mixture. The reaction mixture was stirred at roomtemperature for 4 hours and then at 0° C. overnight, and the reactionwas complete. The reaction mixture was filtered and the solid was washedwith dichloromethane (20 mL×5). The filtrate was concentrated and theresidue was purified by ISCO chromatography to give4-carbamoyl-4-[4-(4-methanesulfonyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a white solid (310 mg, 70% yield): LCMS MH=461.

Step 2: KOtBu (75.2 mg, 0.67 mmol) was added to the stirred solution of4-carbamoyl-4-[4-(4-methanesulfonyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (310 mg, 0.67 mmol) in THF (18 mL) at 0° C. Theresulting mixture was stirred at 0° C. for 1.5 hours and KOtBu (35 mg,0.31 mmol) was added to the reaction mixture. The reaction was stoppedin 30 minutes. To the reaction mixture was added by HCl (1N aq, 10 mL)and the mixture was extracted with dichloromethane (30 mL×2). Organiclayer was dried by MgSO₄ and concentrated under vacuo. The residue waspurified by ISCO chromatography to give a solid. The solid wastriturated with diethyl ether (30 ml) to give3-[4-(4-ethanesulfonyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (195 mg, 68% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 30/70 (acetonitrile/0.1% H₃PO₄):t_(R)=3.98 (98%); mp: 248-250° C.; ¹H NMR DMSO-d₆) δ 1.90-2.08 (m, 1H,CHH), 2.35-2.47 (m, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.81-3.04 (m, 1H,CHH), 3.22 (s, 3H, CH₃), 4.20-4.57 (m, 2H, CHH, CHH), 5.13 (dd, J=5.1,13.2 Hz, 1H, NCH), 5.40 (s, 2H, CH₂), 7.26-7.39 (m, 2H, Ar), 7.48 (d,1H, Ar), 7.76 (d, J=8.3 Hz, 2H, Ar), 7.96 (d, J=8.3 Hz, 2H, Ar), 10.98(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.37, 31.16, 43.45, 45.04, 51.58,68.52, 114.94, 115.51, 127.16, 128.05, 129.86, 129.97, 133.40, 140.27,142.62, 153.13, 167.91, 170.95, 172.81; LCMS MH=429; Anal. Calcd forC₂₁H₂₀N₂O₆S: C, 58.87; H, 4.71; N, 6.54; Found: C, 58.98; H, 4.97; N,6.21.

5.1613-[1-OXO-4-(4-PYRROLIDIN-1-YLMETHYL-BENZYLOXY)-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer-supported triphenylphosphene (1.6 mmol/g, 1.83 g, 2.30mmol) was added to a stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.31 g, 1.04 mmol) in THF (20 mL) at 0° C., followed byaddition of diisopropyl diazene-1,2-dicarboxylate (0.46 ml, 2.30 mmol).After stirring for 30 minutes, (4-pyrrolidin-1-ylmethyl-phenyl)-methanol(0.40 g, 2.09 mmol) was added. The mixture was stirred for one hour thenfiltered, washed with methanol (3×10 mL), then methylene chloride (3×10mL). The combined filtrate was evaporated in vacuo to give an oil, whichwas purified by preparative HPLC to give4-carbamoyl-4-[1-oxo-4-(4-pyrrolidin-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a clear oil (0.17 g, 35% yield).

Step 2: Potassium tert-butoxide (0.08 g, 0.74 mmol) was added to astirred solution of4-carbamoyl-4-[1-oxo-4-(4-pyrrolidin-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.17 g, 0.37 mmol) in THF (10 mL) at 0° C. Themixture was stirred for ten minutes and quenched with 1N HCl (3 mL),neutralized by saturated sodium bicarbonate (6 mL to pH=7), and quicklyextracted by ethyl acetate (2×15 mL). The combined ethyl acetate phaseswere evaporated to a light green foamy oil, which was stirred in water(15 mL) for one hour, filtered and dried to give3-[1-oxo-4-(4-pyrrolidin-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas an off-white solid (0.033 g, 20% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 m, 1 mL/min, 240 nm, isocratic at 15/85 in 10 min(acetonitrile/0.1% H₃PO₄), 5.51 min (98.2%); mp: N/A due to limitedsample available; ¹H NMR (DMSO-d₆) δ 1.64-1.84 (m, 4H, CH₂CH₂),1.97-2.12 (m, 1H, CHH), 2.53-2.72 (m, 6H, CHH, CHH, CH₂CH₂), 2.85-3.09(m, 1H, CHH), 3.63 (s, 2H, CH₂), 4.24-4.56 (m, 2H, CH₂), 5.17 (dd,J=5.1, 13.2 Hz, 1H, NCH), 5.28 (s, 2H, CH₂), 7.30-7.62 (m, 7H, Ar),11.03 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.36, 23.10, 31.21, 45.10,51.58, 53.47, 59.29, 69.45, 115.00, 115.21, 127.61, 128.51, 129.81,129.95, 133.31, 135.00, 139.36, 153.51, 168.01, 170.98, 172.83; LCMSMH=434.

5.162 3-(4-(3-NITROBENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a mixture of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (600 mg, 2.05mmol,) and N,N-diisopropylethylamine (358 μL, 2.05 mmol) in anhydrousDMF (10 mL), was added 1-(bromomethyl)-3-nitrobenzene (421 mg, 1.95mmol). The mixture was stirred at room temperature for 16 hours thenheated to 80° C. for 24 hours. The reaction mixture was cooled on an icebath and then transferred to a chilled 0.5N HCl solution (˜120 mL). Asolid formed was collected by filtration and dried in vacuum oven togive 720 mg of crude product. A portion of the crude product waspurified by injection onto a C-18 preparatory HPLC column. The productwas eluted with an acetonitrile/water gradient (0.1% formic acid in bothmobile phases) and fractions were collected by mass trigger. The desiredfractions were combined and concentrated in vacuo to give3-(4-(3-nitrobenzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as awhite solid (60 mg, 37% yield based on portion purified): HPLC: WatersSymmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60acetonitrile/0.1% H3PO4, 4.20 min (99.0%); mp: 237-240° C.; 1H NMR(DMSO-d6) δ 1.86-2.05 (m, 1H, CHH), 2.35-2.48 (m, 1H, CHH), 2.53-2.67(m, 1H, CHH), 2.82-3.01 (m, 1H, CHH), 4.30 (d, J=17.6 Hz, 1H, CHH), 4.46(d, J=17.4 Hz, 1H, CH), 5.12 (dd, J=5.0, 13.1 Hz, 1H, CH), 5.42 (s, 2H,Ar), 7.23-7.45 (m, 2H, Ar), 7.45-7.59 (m, 1H, Ar), 7.66-7.84 (m, 1H,Ar), 7.98 (d, J=7.7 Hz, 1H, Ar), 8.15-8.29 (m, 1H, Ar), 8.29-8.43 (m,1H, Ar), 10.98 (br. s., 1H, NH); 13C NMR (DMSO-d6) δ 22.38, 31.20,45.10, 51.62, 68.33, 115.08, 115.61, 122.18, 122.90, 129.90, 130.00,130.14, 133.45, 134.14, 139.01, 147.86, 153.15, 167.92, 170.96, 172.83;LCMS MH=396; Anal. Calcd. For C₂₀H₁₇N₃O₆+0.9H₂O: C, 58.36; H, 4.60; N,10.21; Found: C, 58.30; H, 4.21; N, 10.05.

5.1634-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YLOXY)METHYL)BENZAMIDE

Step 1: In a 250-mL RB flask, L-glutamine α-tert-butyl ester (7.83 g,32.8 mmol) and N,N-diisopropylethylamine (11.46 ml, 65.6 mmol) wereslurried in acetonitrile (100 mL) at room temperature. The suspensionwas stirred for about 10 minutes and then a solution of methyl2-(bromomethyl)-3-(tert-butyldimethylsilyloxy)benzoate (11.4 g, 29.8mmol,) in acetonitrile (20 mL) was added dropwise over 10 minutes. Thereaction mixture was heated in an oil bath to a slow reflux (˜80° C.)for 4 hours. The reaction mixture was allowed to cool to roomtemperature for about 1 hour and then a solution of cesium fluoride(4.53 g, 29.8 mmol) in water (15 mL) was added. The resulting mixturewas vigorously stirred at room temperature for 1 hour at which pointLCMS indicated desilylation was complete. The reaction mixture wasdiluted with acetonitrile and filtered to remove undissolved solids. Thesolids were washed with additional acetonitrile. The filtrate and washes(total volume 200 mL) were diluted further with EtOAc (300 mL),transferred to a 1-L separatory funnel, and washed with 0.5N AqueousKH₂PO₄ (100 mL, pH ˜5). To the aqueous layer was added 1 N HCl inportions (˜20 mL, pH changed from pH 7-8 to pH ˜5 using pH paper). NaCl(˜10 g) and EtOAc (˜200 mL) were added to aqueous layer. The mixture wasshaken vigorously in a separatory funnel. The organic layers werecombined, washed with brine (50 mL), dried (Na₂SO₄), and concentrated onrotovap to give 15 g of an off-white solid. This solid containing thecrude product was slurried in acetonitrile (200 mL) and the suspensionwas heated in an oil bath to reflux (˜85° C.) for about 30 minutes withstirring. The mixture was allowed to cool down to room temperature over1 hour then aged at 4° C. for another 2 hours. The solid formed wascollected by suction filtration. The remaining solid in the flask wastransferred onto a filter funnel using some MTBE. The cake was washedwith additional MTBE (total filtrate volume ˜300 mL), suction dried, andthen placed in a vacuum oven at 40° C. for several hours to affordtert-butyl 5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate asa white solid (7.3 g 72% yield, adjusted for purity of starting materialand product): mp: 198-200° C.; ¹H NMR (DMSO-d₆) δ 1.39 (s, 9H, tBu),1.93-2.14 (m, 3H, CH₂, CHH), 2.15-2.33 (m, 1H, CHH), 4.35 (s, 2H, CH₂),4.61-4.83 (m, 1H, CH), 6.76 (br. s., 1H, NH), 6.97-7.07 (m, 1H, Ar),7.11-7.20 (m, 1H, Ar), 7.26 (br. s., 1H, NH), 7.29-7.36 (m, 1H, Ar),10.10 (s, 1H, OH); ¹³C NMR (DMSO-d₆) 5624.81, 27.56, 31.44, 44.71,54.02, 81.38, 113.72, 117.96, 127.99, 129.36, 133.36, 152.50, 168.36,169.88, 172.94; LCMS MH=335; Anal Calcd for C₁₇H₂₂N₂O₅+0.19H₂O: C,60.45; H, 6.68; N, 8.29; Found: C, 60.44; H, 6.62; N, 8.27.

Step 2: tert-Butyl5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg,0.897 mmol), N,N-diisopropylethylamine (157 μL, 0.897 mmol), and K₂CO₃(124 mg, 0.897 mmol) were slurried in DMF (5 mL). After 10 minutes,4-(bromomethyl)benzamide (192 mg, 0.897 mmol) was added and the reactionmixture was stirred at room temperature for 2 days. Removal of DMF invacuo gave a residue that was partitioned between EtOAc and 0.2N aqueousHCl. The aqueous layer was saturated with NaCl and washed withadditional EtOAc. The organic layers were combined (total volume ˜400mL), washed with brine, dried (Na₂SO₄), and concentrated in vacuo togive 400 mg of tert-butyl5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate as an oil.LCMS MH=420. The oil was used in the next step without furtherpurification.

Step 3: To a solution of tert-butyl5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (400 mg) indichloromethane (5 mL) was added TFA (1.5 mL) and the resulting mixturewas stirred at room temperature for 3.5 hours (LCMS indicateddeprotection was complete). The reaction mixture was concentrated invacuo and trace volatiles were chased with a small portion ofdichloromethane (2×) and concentrated again to give 400 mg of4-carbamoyl-2-[4-(4-carbamoyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid as a white solid. This material was used without furtherpurification.4-Carbamoyl-2-[4-(4-carbamoyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid (369 mg, 0.897 mmol, assuming theoretical yield from previous step)was dissolved in DMF (10 mL). To the solution was added CDI (167 mg,1.03 mmol), and the mixture was stirred at room temperature for 12 hoursand then heated to 80° C. for 6 hours. The reaction mixture was cooledon an ice bath and a 0.1N HCl solution was slowly added until a whiteprecipitate was obtained. The solid was filtered and washed with minimalwater, then dried in a vacuum oven to give 150 mg of crude product. Thecrude product was dissolved in DMF and purified by injection onto a C-18preparatory HPLC column. The product was eluted with anacetonitrile/water gradient (0.1% formic acid in both mobile phases, 5%to 60% acetonitrile over 30 minutes) and fractions were collected bymass trigger. The desired fractions were combined and concentrated invacuo to give4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzamideas a white solid (85 mg, 24% combined yield for step 2 and step 3):HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 25/75acetonitrile/0.1% H₃PO₄, 3.41 min (98.8%); mp: 278-280° C.; ¹H NMR(DMSO-d₆) δ 1.89-2.05 (m, 1H, CHH), 2.34-2.48 (m, 1H, CHH), 2.52-2.68(m, 1H, CHH), 2.83-3.01 (m, 1H, CHH), 4.29 (d, J=17.4 Hz, 1H, CHH), 4.45(d, J=17.4 Hz, 1H, CHH), 5.12 (dd, J=5.0, 13.1 Hz, 1H, CH), 5.32 (s, 2H,CH₂), 7.19-7.41 (m, 3H, Ar, NH), 7.43-7.52 (m, 1H, Ar), 7.56 (d, J=8.1Hz, 2H, Ar), 7.89 (d, J=8.3 Hz, 2H, Ar), 7.97 (br. s., 1H, NH), 10.98(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ21.27, 30.11, 44.00, 50.50, 67.88,113.91, 114.26, 126.08, 126.53, 128.72, 128.91, 132.26, 132.79, 138.72,152.21, 166.42, 166.87, 169.88, 171.73; LCMS MH=394; Anal. Calcd. ForC₂₁H₁₉N₃O₅+0.8H₂O+0.28 acetonitrile+1.1 HCOOH: C, 57.57; H, 4.68; N,9.95; Found: C, 57.92; H, 5.07; N, 9.78.

5.1643-(4-(4-CHLORO-3-METHYLBENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: To a solution of 4-chloro-3-methylbenzoic acid (1 g, 5.86 mmol)in THF (10 mL), was slowly added the borane solution in THF (1M, 8.79mL, 8.79 mmol), and the mixture was stirred at room temperatureovernight. The reaction was quenched by adding water (1 mL) dropwise,and then 30 mL of water was added. The mixture was saturated with excesspotassium carbonate, extracted with ethyl acetate (2×50 mL), thecombined organic layers were dried over MgSO₄, and the solvent wasevaporated under vacuum to give (4-chloro-3-methylphenyl)methanol (900mg, 98% yield). ¹H NMR (DMSO-d₆) δ 2.32 (s, 3H, CH₃), 4.45 (d, J=5.7 Hz,2H, CH₂), 5.22 (t, J=5.7 Hz, 1H, OH), 7.15 (dd, J=1.6, 8.2 Hz, 1H, Ar),7.28 (s, 1H, Ar), 7.34 (d, J=8.1 Hz, 1H, Ar).

Step 2: Polymer-supported triphenylphosphine (3 mmol/g, 0.69 g, 2.06mmol) was added to a stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-opentanoate (300 mg, 1.03mmol) in THF (10 mL) at 0° C., followed by diisopropyl azodicarboxylate(416 mg, 2.06 mmol). After stirring for 10 minutes,(4-chloro-3-methylphenyl)methanol (322 mg, 1.03 mmol) was added. Themixture was stirred at room temperature overnight and filtered. Theresin was washed with ethyl acetate (7×10 mL). The combined filtrate waswashed with water and brine, the solvent was evaporated, and the crudewas purified by ISCO (40 g column, MeOH/CH₂Cl₂ gradient from 0% to 3% in40 min) to give methyl5-amino-4-(4-(4-chloro-3-methylbenzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(430 mg, 97% yield). ¹H NMR (DMSO-d₆) δ 2.25 (d, 4H, CH₂, CH₂), 2.35 (s,3H, CH₃), 3.50 (s, 3H, CH₃), 4.33-4.63 (m, 2H, CH₂), 4.69-4.78 (m, 1H,CH), 5.21 (s, 2H, CH₂), 7.19 (s, H, NH), 7.24-7.39 (m, 3H, Ar),7.39-7.51 (m, 3H, Ar), 7.59 (br. s., 1H, NH).

Step 3: To a solution of methyl5-amino-4-(4-(4-chloro-3-methylbenzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoatein THF (10 mL), was added potassium tert-butoxide (112 mg, 1 mmol) at 0°C., and the mixture was stirred at 0° C. for 10 minutes, warmed up toroom temperature, and stirred for 3 hours. The reaction was quenched byadding aqueous HCl (1N, 2 mL). The mixture was diluted with water (30mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine (20 mL), dried over MgSO₄, the solvent wasevaporated under vacuum, and the crude was reslurried in acetonitrile (5mL) for 2 hours and filtered to give3-(4-(4-chloro-3-methylbenzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (180 mg, 45% yield); mp: 217-219° C.; ¹H NMR (DMSO-d₆)δ 2.35 (s, 3H, CH₃), 2.48 (br. s., 1H, CHH), 2.61 (br. s., 1H, CHH),2.80-3.03 (m, 1H, CHH), 4.19-4.52 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2Hz, 1H, CHH), 5.21 (s, 2H, CH₂), 7.25-7.39 (m, 3H, Ar), 7.39-7.57 (m,3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 19.56, 22.34, 31.16,45.07, 51.58, 68.77, 114.97, 115.32, 126.87, 128.88, 129.80, 129.95,130.43, 132.77, 133.33, 135.52, 135.66, 153.32, 167.96, 170.96, 172.81;LCMS MH=399; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240nm, 50/50 acetonitrile/0.1% H₃PO₄ t_(R)=5.29 (99.50%); Anal. Calcd forC₂₁H₁₉ClN₂O₄: C, 63.24; H, 4.80; N, 7.02; Found: C, 62.99; H, 4.94; N,6.86.

5.165 3-(1-OXO-4-(4-(TRIFLUOROMETHYL)BENZYLOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a mixture of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.10 g, 0.34mmol) and K₂CO₃ (0.05 g, 0.34 mmol) in DMF (10 mL), was slowly added4-(trifluoromethyl)benzyl bromide (0.07 g, 0.31 mmol). The reactionmixture was stirred at room temperature overnight. Additional4-(trifluoromethyl)benzyl bromide (0.008 g, 0.03 mmol) was added, andthe reaction mixture was stirred at room temperature overnight.Additional K₂CO₃ (0.05 g, 0.34 mmol) was added, and the reaction mixturewas heated at 80° C. for 24 hours. Acetic acid (5 drops) was added tothe reaction mixture. The solvent was evaporated and ethyl acetate (100mL) was added to the reaction mixture. It was then washed with asaturated solution of sodium bicarbonate (2×100 mL) and brine (100 mL),and dried (MgSO4). After filtration of the drying agent, solvent wasconcentrated down and the residue was purified by ISCO flash (40 gcolumn, gradient methanol/methylene chloride 0/100 to 5/95 in 20 min,eluting product at 5/95). The solvent was evaporated. The residue wasstirred in ether, and solid was filtered and dried to give3-(1-oxo-4-(4-(trifluoromethyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (0.09 g, 72% yield). This experiment was repeated with5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.30 g, 1.03mmol) to give3-(1-oxo-4-(4-(trifluoromethyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dione(0.12 g) and another time with5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.10 g, 0.34mmol) to give3-(1-oxo-4-(4-(trifluoromethyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dione(0.05 g). The 3 batches were combined. Solids were dissolved in ethylacetate (20 mL). The solvent was evaporated. The residue was stirred inether, and solid was filtered and dried to give3-(1-oxo-4-(4-(trifluoromethyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (0.24 g): HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm,1 mL/min, 240 nm, acetonitrile/0.1% H3PO4: gradient 10/90 to 90/10 in 15min; 5 min at 90/10: 12.68 min (98.97%); mp: 241-243° C.; 1H NMR(DMSO-d6) □ 1.17 (t, J=7.1 Hz, 1H, Ethyl Acetate (5%)), 1.82-2.18 (m,1H, CHH), 2.29-2.47 (m, 1H, CHH), 2.58 (d, J=19.1 Hz, 1H, CHH),2.79-3.12 (m, 1H, CHH), 4.03 (d, J=7.2 Hz, 1H, Ethyl Acetate (5%)),4.17-4.39 (m, 1H, CHH), 4.38-4.69 (m, 1H, CHH), 5.13 (dd, J=5.0, 13.1Hz, 1H, CH), 5.38 (s, 2H, CH2), 7.33 (dd, J=7.8, 10.5 Hz, 2H, Ar),7.41-7.59 (m, 1H, Ar), 7.75 (q, J=8.3 Hz, 4H, Ar), 10.99 (s, 1H, NH);13C NMR (DMSO-d6) □ 22.37, 31.16, 45.03, 51.56, 68.58, 114.94, 115.47,124.16 (q, J=270.8 Hz), 125.33 (q, J=3.8 Hz), 128.01, 128.41 (q, J=31.5Hz), 129.84, 129.96, 133.39, 141.52, 153.17, 167.91, 170.96, 172.81;LCMS MH=419; Anal Calcd for C21H17N2O4F3+0.2H2O: C, 59.77, H, 4.16, N,6.64; Found: C, 59.66, H, 4.12, N, 6.52.

5.1663-[4-(3-BROMO-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: tert-Butyl5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (300 mg,0.897 mmol,), N,N-diisopropylethylamine (157 μL, 0.897 mmol), and K₂CO₃(124 mg, 0.897 mmol) were slurried in DMF (5 mL). After 10 minutes,1-bromo-3-bromomethyl-benzene (224 mg, 0.897 mmol) was added and thereaction mixture was stirred at room temperature for 2 days. Removal ofDMF in vacuo gave a residue that was partitioned between EtOAc and 0.2Naqueous HCl. The EtOAc layer was washed with brine, dried (Na₂SO₄), andconcentrated in vacuo to give 450 mg of2-[4-(3-bromo-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid tert-butyl ester as a tan oil. LCMS MH=503, 505. The oil was usedin the next step without further purification.

Step 2: To a solution of2-[4-(3-bromo-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid tert-butyl ester (450 mg) in dichloromethane (5 mL), was added TFA(1.5 mL), and the resulting mixture was stirred at room temperature for4 hours (LCMS indicated deprotection was complete). The reaction mixturewas concentrated in vacuo and the resulting solid was triturated withEt₂O and then collected by filtration. Drying of the solid in vacuoprovided 400 mg of2-[4-(3-bromo-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid as a tan solid. This material was used without furtherpurification.

Step 3: To a solution of2-[4-(3-bromo-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid (400 mg, 0.897 mmol, assuming theoretical yield from previous step)in DMF (5 mL), was added CDI (145 mg, 0.897 mmol). The reaction mixturewas warmed to 70° C. and stirred overnight. After 21 hours, catalyticDMAP was added, followed by another equivalent of CDI. The mixture wasstirred at 80° C. for an additional 15 hours. The reaction mixture wascooled on an ice bath and the crude product was precipitated by additionof 0.2N aqueous HCl. The solid was collected by filtration, washed withcopious water, and dried in vacuo to give 150 mg of crude product. Thecrude product was dissolved in DMF and purified by injection onto a C-18preparatory HPLC column. The product was eluted with anacetonitrile/water gradient (0.1% formic acid in both mobile phases) andfractions were collected by mass trigger. The desired fractions werecombined and concentrated in vacuo to give3-[4-(3-bromo-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (80 mg, 21% combined yield for step 1 and step 2):HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 50/50acetonitrile/0.1% H₃PO₄, 4.59 min (95.5%); mp: 238-240° C.; ¹H NMR(DMSO-d₆) δ 1.89-2.05 (m, 1H, CHH), 2.36-2.48 (m, 1H, CHH), 2.53-2.65(m, 1H, CHH), 2.81-3.02 (m, 1H, CHH), 4.28 (d, J=17.4 Hz, 1H, CHH), 4.45(d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.26 (s, 2H,CH₂), 7.25-7.42 (m, 3H, Ar), 7.45-7.59 (m, 3H, Ar), 7.70 (d, J=1.7 Hz,1H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.26, 31.09, 45.00,51.51, 68.48, 114.87, 115.34, 121.61, 126.52, 129.75, 129.88, 130.15,130.61, 130.74, 133.30, 139.36, 153.15, 167.86, 170.88, 172.74; LCMSMH=429, 431; Anal Calcd for C₂₀H₁₇N₂O₄+0.8H₂O: C, 54.14; H, 4.23; N,6.31; Br, 18.01; Found: C, 53.92; H, 3.88; N, 6.32; Br, 18.16.

5.1674-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YLOXY)METHYL)-N,N-DIMETHYLBENZENESULFONAMIDE

Step 1: To a solution of 4-(N,N-dimethylsulfamoyl)benzoic acid (1 g,4.36 mmol) in THF (10 mL), was slowly added the borane solution in THF(1M, 8.72 mL, 8.72 mmol), and the mixture was stirred at roomtemperature overnight. The reaction was quenched by adding water (1 mL)dropwise, and then 30 mL of water was added. The mixture was saturatedwith excess potassium carbonate and extracted with ethyl acetate (3×40mL), and the combined organic layers were dried over MgSO₄. The solventwas evaporated under vacuum to give4-(hydroxymethyl)-N,N-dimethylbenzenesulfonamide (700 mg, 75% yield). ¹HNMR (DMSO-d₆) δ 2.59 (s, 6H, CH₃, CH₃), 4.61 (d, J=5.9 Hz, 2H, CH₂),5.44 (s, 1H, OH), 7.54-7.62 (m, 2H, Ar), 7.67-7.75 (m, 2H, Ar).

Step 2: Polymer-supported triphenylphosphine (3 mmol/g, 0.69 g, 2.06mmol) was added to a stirred suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-opentanoate (300 mg, 1.03mmol) in THF (10 mL) at 0° C., followed by diisopropyl azodicarboxylate(416 mg, 2.06 mmol). After stirring for 10 minutes,4-(hydroxymethyl)-N,N-dimethylbenzenesulfonamide (443 mg, 2.06 mmol) wasadded. The mixture was stirred at room temperature overnight andfiltered. The resin was washed with ethyl acetate (7×10 mL). Thecombined filtrate was washed with water and brine, the solvent wasevaporated, and the crude was purified by ISCO (40 g column, MeOH/CH₂Cl₂gradient from 0% to 4% in 40 min) to give methyl5-amino-4-(4-(4-(N,N-dimethylsulfamoyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(340 mg, 68% yield). ¹H NMR (DMSO-d₆) δ 1.93-2.36 (m, 4H, CH₂, CH₂),2.62 (s, 6H, CH₃, CH₃), 3.50 (s, 3H, CH₃), 4.40-4.66 (m, 2H, CH₂), 4.75(dd, J=4.7, 10.2 Hz, 1H, CHH), 5.39 (s, 2H, CH₂), 7.21 (s, 1H, NHH),7.27-7.36 (m, 2H, Ar), 7.43-7.53 (m, 1H, Ar), 7.60 (s, 1H, NHH),7.73-7.85 (m, 4H, Ar).

Step 3: To a solution of methyl5-amino-4-(4-(4-(N,N-dimethylsulfamoyl)benzylox-yl)-1-oxoisoindolin-2-yl)-5-oxopentanoate(573 mg, 1.17 mmol) in THF (20 mL), was added potassium tert-butoxide(131 mg, 1 mmol) at 0° C. The mixture was stirred at 0° C. for 10minutes, warmed up to room temperature and stirred for 4 hours.Additional potassium t-butoxide (40 mg, 0.4 mmol) was added, and themixture was kept stirring for 2 hours. The reaction was quenched byadding aqueous HCl (1N, 2 mL), and water (50 mL) was added dropwise. Theprecipitate formed was corrected by filtration, and the crude wasreslurried with acetonitrile (10 mL) to give4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)-N,N-dimethylbenzenesulfonamideas a white solid (260 mg, 48% yield); mp: 261-263° C.; ¹H NMR (DMSO-d₆)δ 1.90-2.10 (m, 1H, CHH), 2.34-2.48 (m, 1H, CHH), 2.56 (d, J=3.4 Hz, 1H,CHH), 2.62 (s, 6H, CH₃, CH₃), 2.82-3.03 (m, 1H, CHH), 4.25-4.56 (m, 2H,CH₂), 5.13 (dd, J=4.9, 13.2 Hz, 1H, CHH), 5.39 (s, 2H, CH₂), 7.28-7.41(m, 2H, Ar), 7.45-7.57 (m, 1H, Ar), 7.73-7.83 (m, 4H, Ar), 10.99 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 22.37, 31.15, 37.51, 45.04, 51.56, 68.56,114.99, 115.54, 127.71, 127.95, 129.87, 129.96, 133.37, 134.20, 142.02,153.19, 167.94, 170.96, 172.84; LCMS MH=458; HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 acetonitrile/0.1% H₃PO₄t_(R)=3.61 (98.56%); Anal. Calcd for C₂₂H₂₃N₃O₆S+0.5H₂O: C, 56.64; H,5.19; N, 9.01; Found: C, 56.62; H, 5.18; N, 8.89.

5.1683-[4-(3-AMINO-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

To a slurry of3-(4-(3-nitrobenzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (300mg, 0.759 mmol) in ethanol (10 mL), was added a solution of sodiumdithionite (661 mg, 3.79 mmol) in water (5 mL). The mixture was stirredfor 20 minutes at room temperature then concentrated in vacuo. Theresidue was dissolved in DMF, the solution passed through a syringefilter, and the filtrate injected onto a C-18 preparatory HPLC column.The product was eluted with an acetonitrile/water gradient (0.1% formicacid in both mobile phases, 5% to 60% acetonitrile over 20 min) andfractions were collected by mass trigger. The desired fractions werecombined and concentrated in vacuo to give3-[4-(3-amino-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione(10 mg, 3% yield) as a white solid: HPLC: Waters Symmetry C₁ s, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 15/85 acetonitrile/0.1% H₃PO₄, 4.17 min(95.6%); mp; 109-113° C.; ¹H NMR (DMSO-d₆) δ 1.87-2.07 (m, 1H, CHH),2.36-2.48 (m, 1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.81-3.02 (m, 1H, CHH),4.25 (d, J=17.6 Hz, 1H, CHH), 4.41 (d, J=17.4 Hz, 1H, CHH), 5.00-5.20(m, 5H, CH₂, NH₂, CH), 6.46-6.55 (m, 1H, Ar), 6.59 (d, J=7.6 Hz, 1H,Ar), 6.62-6.70 (m, 1H, Ar), 7.01 (t, J=7.7 Hz, 1H, Ar), 7.30 (dd, J=7.6,9.8 Hz, 2H, Ar), 7.41-7.53 (m, 1H, Ar), 10.94 (br. s., 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.38, 31.21, 45.10, 51.58, 69.95, 112.74, 113.49, 114.84,114.98, 115.08, 128.93, 129.78, 129.87, 133.26, 137.14, 148.80, 153.60,168.02, 170.99, 172.83; LCMS MH=366; Anal Calcd for C₂₀H₁₉N₃O₄: C,65.74; H, 5.24 N, 11.50; Found: C, 58.81; H, 5.20; N, 9.99.

5.1693-[4-(3,4-DIFLUORO-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: A solution of 3-acetoxy-2-bromomethyl-benzoic acid methyl ester(1.0 g, 3.48 mmol) in acetonitrile (10 mL) was added to a stirredsuspension of tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride andN,N-diisopropylethylamine (1.4 mL, 7.66 mmol) in acetonitrile (20 mL).The mixture was stirred at room temperature for 3.5 hours at roomtemperature. Acetic acid (0.5 mL) was added and the temperature wasraised to 60° C. After 3 days, water (2 mL) was added to the reactionmixture, the temperature was raised to 80° C., and the mixture stirredfor another 3 days. The reaction mixture was cooled to room temperature.Piperidine (1 mL) was added, and stirring was continued for anadditional 6 hours at room temperature. The mixture was concentrated invacuo to remove most volatiles. The resulting viscous oil waspartitioned between EtOAc (200 mL) and 0.2N HCl (50 mL). The aqueouslayer was extracted with additional EtOAc (150 mL). The EtOAc layerswere combined, dried (Na₂SO₄), and concentrated on a rotovap to give1.16 g of crude product as an off-white foam. Purification of this foamon a SiO₂ flash column (CombiFlash, 40 g SiO₂ prepacked column,EtOAc/Hexanes gradient) furnished4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidtert-butyl ester as a white foam (740 mg, 63% yield). LCMS MH=335. ¹HNMR (DMSO-d₆) δ 1.24-1.37 (m, 9H, tBu), 1.81-2.06 (m, 3H, CHH, CH₂),2.08-2.27 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.49 (d, J=17.4Hz, 1H, CHH), 4.71 (dd, J=4.1, 10.1 Hz, 1H, CH), 6.88-7.04 (m, 1H, Ar),7.08-7.23 (m, 2H, Ar, NH), 7.26-7.40 (m, 1H, Ar), 7.55 (br. s., 1H, NH),10.02 (s, 1H, OH).

Step 2: A slurry of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidtert-butyl ester (250 mg, 0.748 mmol), N,N-diisopropylethylamine (130μl, 0.748 mmol), and Cs₂CO₃ (244 mg, 0.748 mmol) in DMF (5 mL) wasstirred for 10 minutes at room temperature, followed by addition of4-chloromethyl-1,2-difluoro-benzene (122 mg, 0.748 mmol). The mixturewas stirred at room temperature for 15 hours then concentrated in vacuoto give crude4-carbamoyl-4-[4-(3,4-difluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid tert-butyl ester as a tan solid (344 mg). This solid was taken upin dry THF (5 mL), and solid KOtBu (84 mg, 0.747 mmol) was added in oneportion with stirring. The mixture was stirred at room temperature for40 minutes, then the reaction was quenched by addition of 1 N aqueousHCl (15 mL). The resulting slurry was diluted further with water, andthe solid collected by filtration, washed with additional water, andsuction dried on filter funnel. The solid was dissolved in minimal DMFand purified by injection onto a C-18 preparatory HPLC column. Theproduct was eluted with an acetonitrile/water gradient (0.1% formic acidin both mobile phases) and fractions were collected by mass trigger. Thedesired fractions were combined and concentrated in vacuo to give3-[4-(3,4-difluoro-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione(140 mg, 48% yield) as a white solid: HPLC: Waters Symmetry C₁₈, 5 jpm,3.9×150 mm, 1 ml/min, 240 nm, 40/60 acetonitrile/0.1% H₃PO₄, 5.53 min(97.9%); mp: 228-230° C.; ¹H NMR (DMSO-d₆) δ 1.90-2.08 (m, 1H, CHH),2.32-2.48 (m, 1H, CHH), 2.52-2.67 (m, 1H, CHH), 2.81-3.00 (m, 1H, CHH),4.28 (d, J=17.6 Hz, 1H, CHH), 4.45 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd,J=5.1, 13.2 Hz, 1H, CH), 5.24 (s, 2H, CH₂), 7.23-7.41 (m, 3H, Ar),7.41-7.54 (m, 2H, Ar), 7.59 (ddd, J=1.9, 8.0, 11.4 Hz, 1H, Ar), 10.97(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.34, 31.16, 45.04, 51.56, 68.17,114.93, 115.44, 116.76 (d, J_(C-F)=17.6 Hz), 117.52 (d, J_(C-F)=17.6Hz), 124.52 (dd, J_(C-F)=3.3, 6.6 Hz), 129.81, 130.00, 133.36, 134.42(dd, J_(C-F)=3.3, 5.5 Hz), 149.12 (dd, J_(C-F)=23.2, 245.3 Hz), 149.44(dd, J_(C-F)=23.2, 245.8 Hz), 153.14, 167.93, 170.95, 172.81; LCMSMH=387; Anal Calcd for C₂₀H₁₆F₂N₂O₄+0.7H₂O: C, 60.21; H, 4.39; N, 7.00;F, 9.52; Found: C, 60.13; H, 4.09; N, 6.91; F, 9.45.

5.170 3-(4-(4-ETHYLBENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a mixture of triphenylphosphine polymer supported (0.75 g, 2.26 mmol)and methyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.30 g, 1.03 mmol) in THF (20 mL) cooled down to 0° C., was added dropwise DIAD (0.45 ml, 2.26 mmol). 4-Ethylbenzyl alcohol (0.16 mL, 1.23mmol) was then added. The reaction mixture was stirred at 0° C. for 1hour and then at room temperature overnight. The reaction mixture wasthen filtered through celite. Celite was washed with ethyl acetate (100mL). The ethyl acetate phase was washed with water, dried with MgSO₄,and solvent was evaporated. The residue was purified by ISCO flash (40 gcolumn, gradient EtOAc/Hexanes 50/50 to 100/0 in 20 min, eluting productat 100/0). The solvent was evaporated and methyl5-amino-4-(4-(4-ethylbenzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoatewas obtained as a sticky, transparent solid (0.20 g, 48% yield). To thesolid stirred in THF (10 mL) and cooled down to 0° C., was added KOtBu(0.05 g, 0.46 mmol), and the reaction mixture was stirred for 3 hours.Acetic acid (I mL) was added to reaction mixture. Ethyl acetate (100 mL)was added, and it was washed with a saturated solution of sodiumbicarbonate (2×100 mL) and brine (100 mL), and dried (MgSO₄). Afterfiltration of the drying agent, solvent was concentrated down to give3-(4-(4-ethylbenzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione as awhite solid (0.12 g, 69% yield): HPLC: Waters Symmetry C18, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, gradient: acetonitrile/0.1% H3PO4, 10/90to 90/10 in 15 min, 90/10 for 5 min, 12.96 min (98.16%); mp: 158-160°C.; 1H NMR (DMSO-d6) δ 1.17 (t, J=7.6 Hz, 3H, CH3), 1.82-2.13 (m, 1H,CHH), 2.31-2.47 (m, 1H, CHH), 2.53-2.72 (m, 3H, CHH, CH2), 2.78-3.10 (m,1H, CHH), 4.24 (d, J=17.4 Hz, 1H, CHH), 4.40 (d, J=17.6 Hz, 1H, CHH),5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 5.20 (s, 2H, CH2), 6.83-7.95 (m, 7H,Ar), 10.97 (s, 4H, NH); 13C NMR (DMSO-d6) δ 15.58, 22.33, 27.85, 31.18,45.06, 51.55, 69.44, 114.96, 115.15, 127.82, 127.86, 129.77, 129.93,133.27, 133.82, 143.59, 153.48, 167.99, 170.96, 172.81; LCMS MH=379;Anal. Calcd for C₂₂H₂₂N₂O₄+0.7H₂O: C, 67.57; H, 6.03; N, 7.16; Found: C,67.40; H, 5.87; N, 7.12.

5.1713-[4-(4-HYDROXYMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: A slurry of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidtert-butyl ester (1.5 g, 4.49 mmol), N,N-diisopropylethylamine (784 μl,4.49 mmol), and K₂CO₃ (620 mg, 4.49 mmol) in DMF (15 mL) was stirred for5 minutes at room temperature, followed by addition of(4-chloromethyl-phenyl)-methanol (902 mg, 4.49 mmol). The mixture wasstirred at room temperature for 15 hours then heated to 70° C. for 3hours. Piperidine (800 μl) was added to the mixture to scavengeunconsumed (4-chloromethyl-phenyl)-methanol. The mixture was stirred foran additional 18 hours at 70° C. The mixture was diluted with water (50mL) and EtOAc (200 mL). The pH of the aqueous was adjusted to 4 using 1N HCl, and the phases were split in a separatory funnel. The aqueouslayer was saturated with NaCl and extracted with additional EtOAc (200mL). The organic layers were combined, washed with brine, dried(Na₂SO₄), and concentrated on rotovap to give 3.5 g of a tan oil. Aportion of this oil (2.1 g) was purified on a SiO₂ flash column(CombiFlash, 80 g SiO₂ prepacked column, MeOH/dichloromethane gradient)to give4-carbamoyl-2-[4-(4-hydroxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid tert-butyl ester as a white foam (1.1 g, 90% yield, based onportion purified): ¹H NMR (DMSO-d₆) δ 1.39 (s, 9H, tBu), 2.00-2.13 (m,3H, CHH, CH₂), 2.13-2.31 (m, 1H, CHH), 4.41 (s, 2H, CH₂), 4.50 (d, J=5.7Hz, 2H, CH₂), 4.69 (dd, J=4.6, 10.3 Hz, 1H, CH), 5.19 (t, J=5.7 Hz, 1H,OH), 5.24 (s, 2H, CH₂), 6.75 (br. s., 1H, NH), 7.22 (br. s., 1H, NH),7.25-7.37 (m, 4H, Ar), 7.42-7.53 (m, 3H, Ar); ¹³C NMR (DMSO-d₆) δ 24.69,27.56, 31.50, 44.78, 54.08, 62.60, 69.45, 81.42, 114.97, 115.18, 126.52,127.57, 129.71, 130.03, 133.27, 134.86, 142.40, 153.42, 168.12, 169.85,172.94; LCMS MH=455.

Step 2: KOtBu (1.1 mL, 1.1 mmol, 1M in THF) was added via syringe to astirred mixture of4-carbamoyl-2-[4-(4-hydroxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid tert-butyl ester (500 mg, 1.1 mmol) in TNF (20 mL). The resultingmixture was stirred at room temperature for 1 hour and then another 100μl of KOtBu was added. After 6 hours, the reaction mixture was quenchedby transferring to 1 N aqueous HCl solution (10 mL). The mixture wasdiluted with EtOAc (150 mL) and 1 N NaHCO₃ (35 mL). The aqueous layerwas washed with additional EtOAc (100 mL). The organic layers werecombined, washed with brine, dried (Na₂SO₄), and concentrated on arotovap to give the crude product as a solid (300 mg). A portion of thesolid (˜127 mg) was dissolved in minimal DMF and purified by injectiononto a C-18 preparatory HPLC column. The product was eluted with anacetonitrile/water gradient (0.1% formic acid in both mobile phases, 5%to 60% acetonitrile over 20 min) and fractions were collected by masstrigger. The desired fractions were combined, concentrated in vacuo, andresidual water was lyophilized to give3-[4-(4-hydroxymethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas white solid (115 mg, 55% yield, based on portion purified): HPLC:Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70acetonitrile/0.1% H₃PO₄, 3.30 min (97.2%); mp: 220-222° C.; ¹H NMR(DMSO-d₆) δ 1.91-2.04 (m, 1H, CHH), 2.34-2.48 (m, 1H, CHH), 2.52-2.64(m, 1H, CHH), 2.81-2.99 (m, 1H, CHH), 4.25 (d, J=17.6 Hz, 1H, CHH), 4.41(d, J=17.6 Hz, 1H, CHH), 4.50 (d, J=5.5 Hz, 2H, CH₂), 5.10 (dd, J=5.2,13.1 Hz, 1H, CH), 5.18 (t, J=5.8 Hz, 1H, OH), 5.23 (s, 2H, CH₂),7.25-7.38 (m, 4H, Ar), 7.39-7.53 (m, 3H, Ar), 10.96 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.31, 31.18, 45.07, 51.56, 62.60, 69.42, 115.01, 115.18,126.49, 127.52, 129.76, 129.96, 133.28, 134.87, 142.38, 153.43, 167.99,170.96, 172.81. LCMS MH=381; Anal Calcd for C₂₁H₂₀N₂O₅+0.3H₂O: C, 65.38;H, 5.38; N, 7.26; Found: C, 65.44; H, 5.43; N, 7.29.

5.1723-[4-(4-DIETHYLAMINOMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONEFORMIC ACID SALT

To a stirred solution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.50 g, 1.72mmol) in DMF (10 mL), were added potassium carbonate (0.24 g, 1.72 mmol)and (4-bromomethyl-benzyl)-diethyl-amine (0.88 g, 2.42 mmol) in DMF (3mL). The mixture was stirred at room temperature overnight and heated at70° C. for three hours. The mixture was purified by preparative HPLC togive3-[4-(4-diethylaminomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneformic acid salt as an off-white solid (0.15 g, 20% yield); HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 m, 1 mL/min, 240 nm, isocratic at 15/85 in10 min (acetonitrile/0.1% H3PO4), 7.31 min (95.5%); mp: 210-212° C.; 1HNMR (DMSO-d6) δ 0.98 (t, J=7.1 Hz, 6H, 2CH3), 1.92-2.04 (m, 1H, CHH),2.41-2.49 (m, 5H, 2CH2, CH), 2.53-2.63 (m, 1H, CHH), 2.83-2.98 (m, 1H,CHH), 3.56 (s, 2H, CH2), 4.21-4.47 (m, 2H, CH2), 5.11 (dd, J=5.1, 13.2Hz, 1H, NCH), 5.22 (s, 2H, CH2), 7.29-7.39 (m, 4H, Ar), 7.40-7.53 (m,3H, Ar), 10.97 (br. s., 1H, NH); 13C NMR (DMSO-d6) δ 11.95, 22.83,31.68, 45.59, 46.52, 52.06, 56.93, 69.93, 115.46, 115.70, 128.07,129.14, 130.29, 130.42, 133.77, 135.48, 139.85, 153.98, 168.49, 171.45,173.31; LCMS MH=436; Anal. Calcd for C₂₅H₂₉N₃O₄ 2.5HCOOH: C, 59.99; H,6.22; N, 7.63; Found: C, 51.24; H, 5.88; N, 6.38.

5.1733-[4-(4-ETHYLAMINOMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONEHYDROCHLORIDE

Ethyl amine (4.24 mL, 8.48 mmol, 2.0 M in THF) was added to a stirredsolution of4-carbamoyl-4-[4-(4-chloromethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.73 g, 1.70 mmol) in acetonitrile (15 mL) at roomtemperature overnight. The mixture was concentrated and swapped to DMF(10 mL). To the solution was added potassium carbonate (0.23 g, 1.70mmol), and the mixture was heated at 80° C. for three hours. The solventwas evaporated and then stirred in 2 M HCl in ether (5 mL) for one hour,filtered and stirred in methylene chloride (8 mL) for two hours,filtered again and dried in vacuum oven to give3-[4-(4-ethylaminomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dionehydrochloride as a white solid (0.126 g, 29% yield); HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H3PO4),4.89 min (93.2%); mp: 273-275° C.; 1H NMR (DMSO-d6) δ 1.93-2.05 (m, 1H,CHH), 2.36-2.47 (m, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.83-3.01 (m, 3H,CH2, CHH), 4.11 (t, J=5.9 Hz, 2H, CH2), 4.22-4.51 (m, 2H, CH2), 5.11(dd, J=5.1, 13.2 Hz, 1H, NCH), 5.29 (s, 2H, CH2), 7.27-7.38 (m, 2H, Ar),7.43-7.63 (m, 5H, Ar), 9.20 (br. s., 2H, NH2Cl), 10.98 (s, 1H, NH); 13CNMR (DMSO-d6) δ 10.83, 22.38, 31.21, 41.63, 45.12, 49.11, 51.62, 69.01,115.03, 115.33, 127.80, 129.81, 130.00, 130.10, 131.83, 133.35, 137.37,153.30, 167.98, 170.98, 172.85; LCMS MH=408; Anal. Calcd for C₂₃H₂₅N₃O₄HCl+0.5H₂O: C, 60.99; H, 6.01; N, 9.28; Cl, 7.83; Found: C, 60.65; H,6.01; N, 9.12; Cl, 7.66.

5.1743-(4-(4-((CHLOROAMINO)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2.6-DIONEHYDROCHLORIDE

Step 1: To a mixture of triphenylphosphine polymer supported (0.93 g,3.54 mmol) and methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.47 g, 1.61mmol) in THF (20 mL) cooled down to 0° C., was added drop wise DIAD(0.70 ml, 3.54 mmol). 4-Hydroxymethyl-benzyl)-carbamic acid tert-butylester (0.46 g, 1.93 mmol) was then added. The reaction mixture wasstirred at 0° C. for 1 hour and then at room temperature overnight. Thereaction mixture was then filtered through celite. Celite was washedwith ethyl acetate (100 mL). The solvent was evaporated. The residue waspurified by ISCO flash (40 g column, gradient EtOAc/Hexanes 50/50 to100/0 in 30 min, eluting product at 80/20). The solvent was evaporatedand methyl5-amino-4-(4-(4-((tert-butoxycarbonylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoatewas obtained as a sticky, transparent solid (0.34 g, 41% yield). To thesolid stirred in THF (15 mL) and cooled down to 0° C., was added KOtBu(0.07 g, 0.65 mmol) and the reaction mixture was stirred for 1.5 hours.Acetic acid (I mL) was added to reaction mixture. Ethyl acetate (100 mL)was added, and it was washed with a saturated solution of sodiumbicarbonate (2×100 mL) and brine (100 mL), and dried (MgSO₄). Afterfiltration of the drying agent, solvent was concentrated down to givetert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzylcarbamateas a light pink solid (0.25 g, 81% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, gradient: acetonitrile/0.1% H₃PO₄,10/90 to 90/10 in 15 min, 90/10 for 5 min, 12.06 min (98.12%).

Step 2: To a solution of tert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzylcarbamate(0.10 g, 0.2 mmol) in THF (40 mL), was bubbled HCl gaz for 15 minutes.The solvent was then evaporated. Water (10 mL) was added to the residue,and it was filtered. The filtrate was concentrated down, and the residuewas stirred in ether overnight. Solid was then filtered and dried inoven at 40° C. to give3-(4-(4-((chloroamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2.6-dionehydrochloride as a white solid (0.08 g, 94% yield); mp: 198-200° C.; ¹HNMR (DMSO-d₆) δ 1.86-2.12 (m, 1H, CHH), 2.34-2.49 (m, 1H, CHH),2.53-2.69 (m, 1H, CHH), 2.81-3.05 (m, 1H, CHH), 4.02 (q, J=5.6 Hz, 2H,CH₂), 4.27 (d, J=17.6 Hz, 1H, CHH), 4.43 (d, J=17.6 Hz, 1H, CHH), 5.11(dd, J=5.1, 13.2 Hz, 1H, CH), 5.28 (s, 2H, CH₂), 7.21-7.40 (m, 2H, Ar),7.40-7.73 (m, 4H, Ar), 8.45 (br. s., 3H, NH₃Cl), 10.97 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 22.33, 31.18, 41.85, 45.09, 51.59, 69.01, 115.00,115.28, 127.77, 129.06, 129.77, 129.97, 133.33, 133.75, 136.87, 153.26,167.96, 170.96, 172.83; LCMS MH=380; Anal. Calcd forC₂₁H₂₂N₃O₄Cl+1.5H₂O: C, 56.95; H, 5.69; N, 9.49; Found: C, 56.81; H,5.61; N, 9.37.

5.175 3-(4-(4-((2-METHOXYETHYLAMINO)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE FORMATE

Step 1: To a solution of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(250 mg, 0.529 mmol) in acetonitrile (10 mL), were added2-methoxyethanamine (0.068 ml, 0.793 mmol) and DIEA (0.138 ml, 0.793mmol). The resulting mixture was stirred at 50° C. for 1.5 hours, thenadditional 2-methoxyethanamine (150 μl) was added. The temperature wasraised to 60° C. and the mixture was stirred for another 2.5 hours. Thereaction mixture was concentrated in vacuo using a rotovap to givetert-butyl5-amino-2-(4-(4-((2-methoxyethylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas a white foam (295 mg, assume theoretical yield). LCMS MH=512. Thesolid was used in the next step without further purification.

Step 2: tert-Butyl5-amino-2-(4-(4-((2-methoxyethylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.528 mmol, assume theoretical yield from previous step) was taken upin dry THF (5 mL). To the stirred suspension at room temperature wasadded KOtBu (0.581 ml, 0.581 mmol, 1.0 M in THF) dropwise. The resultingmixture was stirred at room temperature for 2 hours and then additonalKOtBu (176 μL) was added. The mixture was stirred overnight at roomtemperature, then treated with additional KOtBu (176 μL). After 6 hours,a final portion of KOtBu was added, and the mixture was stirred for 2hours. The reaction mixture was quenched by transferring to a 2 M solnof formic acid in MeCN on an ice bath. The mixture was concentrated invacuo using a rotovap to give an oil which was dissolved in minimal DMFand purified by injection onto a C-18 preparatory HPLC column. Theproduct was eluted with an acetonitrile/water gradient (0.1% formic acidin both mobile phases, 5% to 30% MeCN over 12 minutes) and fractionswere collected by mass trigger. The desired fractions were combined andconcentrated in vacuo, and residual water was lyophilized to give3-(4-(4-((2-methoxyethylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneformate as a white solid (80 mg, 35% yield): HPLC: Waters Symmetry C, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 5% grad 95% in 10 min,acetonitrile/0.1% H₃PO₄, 5.64 min (95.6%); mp: 200-202° C.; ¹H NMR(DMSO-d₆) δ 1.89-2.06 (m, 1H, CHH), 2.35-2.48 (m, 1H, CHH), 2.52-2.62(m, 1H, CHH), 2.65 (t, J=5.6 Hz, 2H, CH₂), 2.82-3.01 (m, 1H, CHH), 3.23(s, 3H, OCH₃), 3.40 (t, J=5.7 Hz, 2H, CH₂O), 3.73 (s, 2H, CH₂N), 4.28(d, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.4 Hz, 1H, CHH), 5.01-5.16 (m, 1H,CH), 5.22 (s, 2H, C H₂O), 7.23-7.39 (m, 4H, Ar), 7.40-7.55 (m, 3H, Ar),8.07-8.55 (m, 1H, HCOOH), 10.39-11.40 (m, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.31, 31.18, 45.07, 47.62, 51.56, 52.33, 57.95, 69.41, 71.33, 114.97,115.18, 127.61, 128.09, 129.77, 129.95, 133.28, 134.92, 140.17, 153.45,167.99, 170.95, 172.81; LCMS MH=438; Anal Calcd forC₂₄H₂₇N₃O₅.HCOOH+2.8H₂O: C, 56.24; H, 6.53; N, 7.87; Found: C, 56.13; H,6.18; N, 7.75.

5.1763-(4-{4-[(METHYL-PHENYL-AMINO)-METHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

N-methylaniline (0.55 ml, 5.00 mmol) was added to a stirred solution ofmethyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.72 g, 1.67 mmol) in DMF (15 ml). The mixture was stirred at 50° C.for two days. To the mixture was added potassium carbonate (0.23 g, 1.67mmol), and the mixture was heated at 70° C. overnight. The reactionmixture was concentrated in vacuo and the residue was purified on silicagel column (CH₂Cl₂/EtOAc gradient from 5% EtOAc in CH₂Cl₂ to 50%) togive3-(4-{4-[(Methyl-phenyl-amino)-methyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (0.29 g, 37% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5min, isocratic at 95/5 in 5 min (acetonitrile/0. % H3PO4): 6.20 min(98.4%); mp: 201-203° C. 1H NMR (DMSO-d6) δ 1.91-1.98 (m, 1H, CHH),2.35-2.47 (m, 1H, CHH), 2.53-2.62 (m, 1H, CHH), 2.82-2.97 (m, 1H, CHH),3.01 (s, 3H, CH3), 4.19-4.45 (m, 2H, CH2), 4.57 (s, 2H, CH2), 5.10 (dd,J=5.2, 13.3 Hz, 1H, NCH), 5.20 (s, 2H, CH2), 6.60 (t, J=7.3 Hz, 1H, Ar),6.70 (dd, J=0.9, 8.9 Hz, 2H, Ar), 7.09-7.18 (m, 2H, Ar), 7.22 (d, J=8.1Hz, 2H, Ar), 7.29-7.36 (m, 2H, Ar), 7.39-7.53 (m, 3H, Ar), 10.96 (s, 1H,NH); 13C NMR (DMSO-d6) δ 22.33, 31.20, 38.60, 45.09, 51.56, 55.05,69.36, 111.99, 114.92, 115.21, 115.84, 126.85, 127.97, 128.95, 129.81,129.95, 133.29, 134.95, 139.02, 148.97, 153.48, 168.01, 170.96, 172.83;LCMS MH=470; Anal. Calcd for C₂₈H₂₇N₃O₄+0.3H2O: C, 70.81; H, 5.86; N,8.85; Found: C, 70.51; H, 5.66; N, 8.71.

5.177 3-(4-(4-((BIS(2-METHOXYETHYL)AMINO)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: To a solution of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(250 mg, 0.529 mmol) in acetonitrile (10 mL), were addedbis(2-methoxyethyl)amine (106 mg, 0.793 mmol) andN,N-diisopropylethylamine (0.138 ml, 0.793 mmol). The resulting mixturewas stirred at 60° C. for 2 days. The mixture was concentrated in vacuousing a rotovap and further dried in a vacuum oven overnight to givetert-butyl5-amino-2-(4-(4-((bis(2-methoxyethyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas an amber oil (320 mg). The oil was used in the next step withoutfurther purification.

Step 2: tert-Butyl5-amino-2-(4-(4-((bis(2-methoxyethyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.528 mmol, assume theoretical yield from previous step) was taken upin dry THF (5 mL). To the stirred suspension at room temperature, KOtBu(0.581 ml, 0.581 mmol, 1.0 M in THF) was added dropwise. The resultingmixture was stirred at room temperature for 48 hours, then additionalKOtBu (200 μL, 0.2 mmol) was added to the reaction, and the mixturestirred for 3 hours. Another portion of KOtBu (400 μL, 0.4 mmol) wasadded (total of 1.18 mmol KOtBu used). After about 15 minutes, LCMSindicated cyclization was complete. The reaction mixture was cooled at0° C. and quenched with formic acid (500 μL) and concentrated using arotovap to give an oily residue, which was dissolved in H₂O and DMF (2mL/6 mL) and filtered on a syringe filter (0.2 g polypropylene). Thefiltrate was purified by injection onto a C-18 preparatory HPLC column.The product was eluted with an acetonitrile/water gradient (0.1% formicacid in both mobile phases, 5% to 30% MeCN over 12 minutes) andfractions were collected by mass trigger. The desired fractions werecombined and concentrated in vacuo and residual water was lyophilized togive3-(4-(4-((bis(2-methoxyethyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas an off-white solid (110 mg, 42% yield for step 1 and step 2): HPLC:Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 20/80acetonitrile/0.1% H₃PO₄, 3.22 min (95.4%); mp: 105-107° C.; ¹H NMR(DMSO-d₆) δ 1.89-2.05 (m, 1H, CHH), 2.35-2.48 (m, 1H, CHH), 2.52-2.60(m, 1H, CHH), 2.62 (t, J=6.1 Hz, 4H, 2×CH₂), 2.80-2.99 (m, 1H, CHH),3.20 (s, 6H, 2×CH₃), 3.39 (t, J=6.1 Hz, 4H, 2×CH₂), 3.62 (s, 2H, CH₂),4.25 (d, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd,J=5.2, 13.1 Hz, 1H, CHH), 5.22 (s, 2H, C H₂O), 7.28-7.37 (m, 4H, Ar),7.38-7.53 (m, 3H, Ar), 10.97 (br. s., 1H, NH); ¹³C NMR (DMSO-d₆) δ22.33, 31.18, 45.07, 51.55, 52.99, 57.98, 58.52, 69.44, 70.57, 114.97,115.18, 127.55, 128.52, 129.77, 129.93, 133.27, 134.95, 139.67, 153.48,167.99, 170.95, 172.81; Anal Calcd for C₂₇H₃₃N₃O₆.+0.7 HCOOH+2H₂O: C,59.01; H, 6.86; N, 7.45; Found: C, 58.72; H, 6.49; N, 7.32.

5.178 tert-BUTYL3-(DIETHYLAMINO)PROPYL(4-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YLOXY)METHYL)BENZYL)CARBAMATE

Step. 1: In a round-bottomed flask was methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.0 g, 2.321 mmol) in acetonitrile (Volume: 30 ml) to give a colorlesssolution. N1,N1-diethylpropane-1,3-diamine (0.907 g, 6.96 mmol) wasadded. The mixture was stirred at room temperature over weekend. Thereaction was concentrated on rota-vap. The resulting oil was used innext step without any purification.

Step 2: To the CH₂Cl₂ solution (30 mL) of methyl5-amino-4-(4-(4-((3-(diethylamino)propylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.218 g, 2.32 mmol), was added BOC₂O (2.70 ml, 11.61 mmol). The mixturewas stirred at room temperature for 2 hours. The reaction mixture wasconcentrated and purified on silica gel column eluted with methylenechloride and methanol to give methyl5-amino-4-(4-(4-((tert-butoxycarbonyl(3-(diethylamino)propyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas a clear oil (500 mg, 35%).

Step 3: To the THF solution (20 mL) of methyl5-amino-4-(4-(4-((tert-butoxycarbonyl(3-(diethylamino)propyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 0.80 mmol), was added potassium tert-butoxide (0.090 g, 0.80mmol). The mixture was stirred at 0° C. for 10 minutes and quenched byadding 1N HCl (2 mL) followed by saturated NaHCO₃ (15 mL) and EtOAc (30mL). The mixture was extracted and separated. The organic layer waswashed with brine and concentrated on rota-vap. The resulting oil waspurified on silica gel column and eluted with CH₂Cl₂/MeOH to givetert-butyl3-(diethylamino)propyl(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)carbamateas a white solid was obtained (0.23 g, 49%). mp: 140-142° C. HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradientacetonitrile/0.1% H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at100/0 for 5 min: t_(R)=5.15 min (95%). ¹H NMR (DMSO-d₆) δ 0.89 (t, J=7.2Hz, 6H, CH₃, CH₃), 1.29-1.47 (m, 9H, CH₃, CH₃, CH₃), 1.48-1.62 (m, 2H,CH₂), 1.89-2.06 (m, 1H, CHH), 2.29 (t, J=7.0 Hz, 2H, CH₂), 2.37 (q,J=7.2 Hz, 4H, CH₂, CH₂), 2.42-2.47 (m, 1H, CHH), 2.54-2.63 (m, 1H, CHH),2.80-2.98 (m, 1H, CHH), 3.00-3.23 (m, 2H, CH₂), 4.03-4.61 (m, 4H, CH₂,CH₂), 4.95-5.18 (m, 1H, NCH), 5.23 (s, 2H, CH₂), 7.12-7.38 (m, 4H, Ar),7.39-7.65 (m, 3H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 11.52,28.01, 31.16, 45.06, 46.01, 49.58, 51.55, 69.29, 78.64, 114.94, 115.20,127.29, 127.83, 129.77, 129.93, 133.28, 135.30, 138.66, 153.42, 167.99,170.95, 172.81; LCMS MH=593. Anal Calcd for C₃₃H₄₄N₄O₆+0.1H₂O: C, 66.87;H, 7.49; N, 9.42; Found: C, 66.40; H, 7.43; N, 9.27.

5.179[{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYL}-(2-MORPHOLIN-4-YL-ETHYL)-AMINO]-ACETICACID TERT-BUTYL ESTER

Step 1: To a stirred colorless solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.18 g, 2.75 mmol) in acetonitrile (15 ml), was added2-morpholinoethanamine (1.08 ml, 8.24 mmol). The reaction mixtureimmediately turned into a light green solution. The reaction was stirredat room temperature overnight. The solution was evaporated to give alight green oil, which was not further characterized and used in thenext step without purification.

Step 2: To a stirred solution of methyl5-amino-4-(4-(4-((2-morpholinoethylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.442 g, 2.75 mmol) in dichloromethane (15 ml), was added di-tert-butyldicarbonate (1.80 g, 8.25 mmol). The weight of the limiting SM wasassumed as 1.44 g, which was the theoretical yield of the previous step.The oil was purified on silica gel column (MeOH/CH₂Cl₂ gradient from 1%to 9% in 50 min) to give4-[4-(4-{[tert-Butoxycarbonylmethyl-(2-morpholin-4-yl-ethyl)-amino]-methyl}-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as an oily solid (0.88 g, 51% over two steps).

Step 3: To a stirred solution of methyl5-amino-4-(4-(4-((tert-butoxycarbonyl(2-morpholinoethyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.36 g, 0.58 mmol) in THF (10 ml) at 0° C., was added potassium2-methylpropan-2-olate (0.07 g, 0.58 mmol). The reaction mixture wasstirred for ten minutes and quenched with 1 N HCl (2 mL) to give a clearcolorless solution. It was neutralized with saturated sodium bicarbonate(to pH=7) to give a cloudy mixture, which was extracted with ethylacetate (2×20 mL). The ethyl acetate phase was concentrated and purifiedon silica gel column (MeOH/CH₂Cl₂ gradient from 1% to 5% in 30 min) togive[{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-(2-morpholin-4-yl-ethyl)-amino]-aceticacid tert-butyl ester as a foamy white solid (0.21 g, 62% yield); HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from10/90 to 95/5 in 5 min, isocratic at 95/5 in 5 min (acetonitrile/0.1%H₃PO₄), 5.38 min (97.4%); mp: 110-112° C.; ¹H NMR (DMSO-d₆) δ 1.29-1.49(m, 9H, 3CH₃), 1.92-2.05 (m, 1H, CHH), 2.25-2.39 (m, 6H, 3CH₂), 2.44(dd, J=4.5, 13.0 Hz, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.83-3.00 (m, 1H,CHH), 3.15-3.29 (m, 2H, CH₂), 3.52 (t, J=4.6 Hz, 4H, 2CH₂), 4.19-4.49(m, 4H, CH₂, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H,CH₂), 7.23-7.37 (m, 4H, Ar), 7.41-7.53 (m, 3H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.36, 28.02, 31.21, 43.30, 45.09, 49.37, 50.05,51.58, 53.33, 55.95, 56.39, 66.17, 69.32, 78.84, 115.00, 115.23, 127.39,127.83, 129.78, 129.97, 133.31, 135.30, 138.56, 153.43, 155.02, 168.01,170.96, 172.83 (2 extra peaks in alkyl region possibly from the twoalkyl atoms close to the amide nitrogen atom due to the rotamer); LCMSMH=593; Anal. Calcd for C₃₂H₄₀N₄O₇+0.1H₂O: C, 64.65; H, 6.82; N, 9.42;Found: C, 64.31; H, 6.82; N, 9.24.

5.180N-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYL}-N-(2-MORPHOLIN-4-YL-ETHYL)-FORMAMIDE

Step 1: To a stirred colorless solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.18 g, 2.75 mmol) in acetonitrile (15 ml), was added2-morpholinoethanamine (1.08 ml, 8.24 mmol). The reaction mixtureimmediately turned into a light green solution. The reaction was stirredat room temperature overnight. The reaction solution was evaporated togive a light green oil, which was not further characterized and used inthe next step without purification.

Step 2: To a stirred solution of methyl5-amino-4-(4-(4-((2-morpholinoethylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.442 g, 2.75 mmol) in dichloromethane (15 ml), was added di-tert-butyldicarbonate (1.80 g, 8.25 mmol). The weight of the limiting SM wasassumed as 1.44 g, which was the theoretical yield of the previous step.The oil was purified on silica gel column (MeOH/CH₂Cl₂ gradient from 1%to 9% in 50 min) to give4-[4-(4-{[tert-Butoxycarbonylmethyl-(2-morpholin-4-yl-ethyl)-amino]-methyl}-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as an oily solid (0.88 g, 51% yield over two steps).

Step 3: To a stirred solution of methyl5-amino-4-(4-(4-((tert-butoxycarbonyl(2-morpholinoethyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.36 g, 0.58 mmol) in THF (10 ml) at 0° C., was added potassium2-methylpropan-2-olate (0.07 g, 0.58 mmol). The reaction mixture wasstirred for ten minutes and was quenched with 1 N HCl (2 mL) to give aclear colorless solution. It was neutralized with saturated sodiumbicarbonate (4 ml to pH=7) to give a cloudy mixture, which was extractedwith ethyl acetate (2×20 mL). The ethyl acetate phase was concentratedand purified on silica gel column (MeOH/CH₂Cl₂ gradient from 1% to 5% in30 min) to give[{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-(2-morpholin-4-yl-ethyl)-amino]-aceticacid tert-butyl ester as a foamy solid (0.213 g, 62% yield); HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from10/90 to 95/5 in 5 min, isocratic at 95/5 in 5 min (acetonitrile/0.1%H₃PO₄), 5.38 min (97.4%); mp: 110-112° C.; ¹H NMR (DMSO-d₆) δ 1.29-1.49(m, 9H, 3CH₃), 1.92-2.05 (m, 1H, CHH), 2.25-2.39 (m, 6H, 3CH₂), 2.44(dd, J=4.5, 13.0 Hz, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.83-3.00 (m, 1H,CHH), 3.15-3.29 (m, 2H, CH₂), 3.52 (t, J=4.6 Hz, 4H, 2CH₂), 4.19-4.49(m, 4H, CH₂, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H,CH₂), 7.23-7.37 (m, 4H, Ar), 7.41-7.53 (m, 3H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.36, 28.02, 31.21, 43.30, 45.09, 49.37, 50.05,51.58, 53.33, 55.95, 56.39, 66.17, 69.32, 78.84, 115.00, 115.23, 127.39,127.83, 129.78, 129.97, 133.31, 135.30, 138.56, 153.43, 155.02, 168.01,170.96, 172.83 (2 extra peaks in alkyl region possibly from the twoalkyl atoms close to the amide nitrogen atom due to the rotamer); LCMSMH=593; Anal. Calcd for C₃₂H₄₀N₄O₇+0.1H₂O: C, 64.65; H, 6.82; N, 9.42;Found: C, 64.31; H, 6.82; N, 9.24.

Step 5: To a stirred solution of tert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl(2-morpholinoethyl)carbamate(0.42 g, 0.71 mmol) in dichloromethane (5 ml), was added 2M HCl/ether (4ml). A white precipitate formed almost immediately. The suspension wasstirred overnight and filtered to give a white solid, which was purifiedby prep HPLC to give a clear oil (0.22 g, 58% yield). It was found to bea mixture of the desired product (16% by H NMR) and the amide on thebenzyl NH with formic acid (84% by H NMR).

Step 6: To a stirred mixture of3-(4-(4-((2-morpholinoethylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.04 g, 0.08 mmol) in dichloromethane (3 ml) at room temperature, wasadded ethyl formate (6.04 μl, 0.075 mmol). It was stirred for one hour,and 0.12 ml of ethyl formate was added and stirred for six hours. Themixture was evaporated to give a white solid, to which was added diethylether (5 mL), stirred and evaporated again to give a white solid. It wasstirred in ethyl acetate (2 mL) and evaporated. It was repeated two moretimes (by adding 2 mL of EtOAc and then evaporated). The resulting whitesolid was dried in vacuum oven overnight to giveN-{4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-N-(2-morpholin-4-yl-ethyl)-formamideas a white solid (0.16 g, 79% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄), 5.23 min(95.4%); mp: 216-218° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.05 (m, 1H, CH),2.23-2.36 (m, 6H, CH₂, CH₂, CH₂), 2.36-2.47 (m, 1H, CH), 2.53-2.66 (m,1H, CH), 2.83-3.00 (m, 1H, CH), 3.20 (t, J=6.6 Hz, 1H, CH), 3.27 (t,J=6.0 Hz, 1H, CH), 3.51 (t, J=4.6 Hz, 4H, ch₂, ch₂), 4.20-4.46 (m, 2H,CH₂), 4.50 (d, J=5.1 Hz, 2H, CH₂), 5.11 (dd, J=5.2, 13.3 Hz, 1H, NCH),5.24 (d, J=6.8 Hz, 2H, CH₂), 7.24-7.37 (m, 4H, ArH), 7.41-7.54 (m, 3H,ArH), 8.15 (s, 0.5H, HCON, due to rotamer), 8.29 (s, 0.5H, HCON, due torotamer), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.36, 31.20, 38.09,43.31, 44.74, 45.08, 50.21, 51.58, 53.14, 55.02, 56.11, 66.11, 66.17,69.29, 115.01, 115.24, 127.78, 127.85, 127.99, 129.79, 129.97, 133.31,135.47, 136.05, 137.11, 137.36, 153.41, 163.00, 163.31, 167.99, 170.96,172.83 (4 extra peaks in aromatic region and 6 extra peaks in alkylregion due to rotamer); LCMS MH=521; Anal. Calcd for C₂₈H₃₂N₄O₆+0.6H₂O:C, 63.29; H, 6.30; N, 10.54; Found: C, 63.06; H, 6.24; N, 10.35.

5.1814-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YLOXY)METHYL)-N-METHYL-N-(2-MORPHOLINOETHYL)BENZAMIDE

Step 1: 4-(chloromethyl)benzoyl chloride (655 mg, 3.47 mmol) was addedto the stirred solution of N-methyl-2-morpholinoethanamine (500 mg, 3.47mmol) in acetonitrile (20 mL). The reaction mixture was stirred at roomtemperature for 15 minutes and the reaction was complete. The reactionmixture was added by NaHCO₃ (aq. sat. 30 mL). The solution was extractedwith EtOAc (40 mL×3). Organic layers were combined and dried by MgSO₄.The mixture was filtered and concentrated to give4-chloromethyl-N-methyl-N-(2-morpholin-4-yl-ethyl)-benzamide as a lightbrown oil (1.0 g, 97% crude yield): LCMS MH=297; ¹H NMR (DMSO-d₆) δ2.07-2.25 (m, 2H, CH₂), 2.32-2.47 (m, 2H, CH₂), 2.82-3.01 (m, 3H, CH₂),3.31 (s, 3H, CH₃), 3.39-3.67 (m, 5H, CH₂), 4.80 (s, 2H, CH₂), 7.39 (d,J=8.1 Hz, 2H, Ar), 7.49 (d, J=8.1 Hz, 2H, Ar).

Step 2: To the stirred mixture of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (400 mg,1.369 mmol), 4-(chloromethyl)-N-methyl-N-(2-morpholino ethyl)benzamide(406 mg, 1.369 mmol) and K₂CO₃ (189 mg, 1.369 mmol) in DMF (10 mL), wasadded DIPEA (0.239 ml, 1.369 mmol). The resulting reaction mixture wasstirred at room temperature for 3 days and then heated at 50° C. for 24hours before it was added by K₂CO₃ (100 mg, 0.82 mmol) and heated at 80°C. for 3.5 hours. The reaction mixture combined with another batch ofreaction with methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (100 mg, 0.34mmol) was concentrated and purified by ISCO chromatography to give4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)-N-methyl-N-(2-morpholinoethyl)benzamideas a white solid (135 mg, 15% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80, (acetonitrile/0.1% H₃PO₄),2.11 min (98%); mp: 120-122° C.; ¹H NMR (DMSO-d₆) δ 1.96-2.09 (m, 1H,CHH), 2.28-2.37 (m, 4H, CH₂, CH₂), 2.39-2.46 (m, 1H, CHH), 2.44-2.52 (m,2H, CH₂), 2.54-2.66 (m, 1H, CHH), 2.79-2.91 (m, 1H, CHH), 2.94 (s, 3H,CH₃), 3.44 (t, J=6.4 Hz, 2H, CH₂), 3.52 (t, J=4.7 Hz, 4H, CH₂, CH₂),4.32 (d, J=17.2 Hz, 1H, CHH), 4.43 (d, J=17.2 Hz, 1H, CHH), 5.04 (dd,J=5.3, 13.0 Hz, 1H, CHH), 5.28 (s, 2H, CH₂), 7.24-7.57 (m, 7H, Ar),10.62 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.36, 31.16, 37.28, 43.50,45.06, 51.56, 53.28, 55.04, 66.16, 69.03, 114.99, 115.32, 126.87,127.29, 129.78, 129.96, 133.33, 136.39, 137.66, 153.32, 167.96, 170.95,172.81; LCMS MH=521; Anal. Calcd for C₂₈H₃₂N₄O₆+1.3H₂O: C, 61.82; H,6.41; N, 10.30; Found: C, 61.73; H, 6.29; N, 10.11.

5.1824-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YLOXY)METHYL)-N-(2-(PIPERIDIN-1-YL)ETHYL)BENZAMIDE

Step 1: 4-(Chloromethyl)benzoyl chloride (1.474 g, 7.80 mmol) was addedto the stirred solution of 2-(piperidin-1-yl)ethanamine (1 g, 7.80 mmol)in acetonitrile (20 mL) at room temperature. The resulting clearsolution was stirred at room temperature for 20 minutes and the reactionwas complete. The reaction mixture was diluted by EtOAc (50 mL) andextracted by NaHCO₃ (aq. sat. 30 mL). The aqueous layer was backextracted with EtOAc (2×25 mL). Organic layers were combined and driedby MgSO₄. The mixture was filtered and concentrated to give4-chloromethyl-N-(2-piperidin-1-yl-ethyl)-benzamide as a light brownsolid (2.46 g, 109% crude yield): LCMS MH=281; ¹H NMR (DMSO-d₆) δ1.29-1.57 (m, 6H, CH₂, CH₂, CH₂), 2.30-2.46 (m, 6H, CH₂, CH₂, CH₂),3.26-3.45 (m, 2H, CH₂), 4.80 (s, 2H, CH₂), 7.51 (d, J=8.3 Hz, 2H, Ar),7.82 (d, J=8.3 Hz, 2H, Ar), 8.40 (t, J=5.5 Hz, 1H, NH).

Step 2: K₂CO₃ (284 mg, 2.053 mmol) was added to the stirred solution ofmethyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (600mg, 2.053 mmol) and4-(chloromethyl)-N-(2-(piperidin-1-yl)ethyl)benzamide (576 mg, 2.053mmol) in DMF (12 mL), followed by the addition of DIPEA (0.359 ml, 2.053mmol) at room temperature. The resulting reaction suspension was stirredat room temperature for 2 days and heated at 50° C. for 1 day beforeK₂CO₃ (120 mg, 0.87 mmol) was added to the reaction. The resultingreaction mixture was heated at 80° C. for 3 hrs and the reaction wascomplete. The reaction mixture was acidified by HCl (1N, 8 mL) to PH=3.The clear solution was added by NaHCO₃ (aq, sat., 8 mL) to pH=8 beforeit was added by dichloromethane (40 mL) and brine (10 mL). The mixturewas extracted and the aqueous layer was back extracted withdichloromethane (30 mL×2). Organic layers were combined and dried byMgSO₄. The mixture was filtered and the filtrate was concentrated. Theresidue was purified by ISCO chromatography to give a white solid (220mg). The solid was dissolved in dichloromethane (2 mL) and precipitatedout in EtOAC (10 mL). The solid was filtered and dried to give4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)-N-(2-(piperidin-1-yl)ethyl)benzamideas a white solid (205 mg, 19.8% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80, (acetonitrile/0.1% H₃PO4),2.91 min (97.6%); mp: 220-222° C.; ¹H NMR (DMSO-d₆) δ 1.31-1.42 (m, 2H,CH₂), 1.43-1.56 (m, 4H, CH₂, CH₂), 1.92-2.06 (m, 1H, CHH), 2.30-2.47 (m,7H, CHH, CH₂, CH₂, CH₂), 2.58 (d, J=17.6 Hz, 1H, CHH), 2.82-3.00 (m, 1H,CHH), 3.34-3.40 (m, 2H, CH₂), 4.28 (d, 1H, CHH), 4.45 (d, J=17.6 Hz, 1H,CHH), 5.12 (dd, J=5.0, 13.1 Hz, 1H, CHH), 5.32 (s, 2H, CH₂), 7.26-7.37(m, 2H, Ar), 7.42-7.52 (m, 1H, Ar), 7.56 (d, J=8.3 Hz, 2H, Ar), 7.84 (d,J=8.3 Hz, 2H, Ar), 8.38 (t, J=5.6 Hz, 1H, NH), 10.98 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 22.34, 23.97, 25.53, 31.18, 36.92, 45.07, 51.58, 54.02,54.93, 57.61, 68.97, 115.01, 115.35, 127.23, 129.78, 129.97, 133.34,134.19, 139.64, 153.27, 165.73, 167.97, 170.96, 172.81; LCMS MH=505;C₂₈H₃₂N₄O₅+0.1H₂O+0.42CH2Cl2: C, 62.92; H, 6.14; N, 10.34; Found: C,62.85; H, 6.26; N, 10.17.

5.1834-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-N-(3-MORPHOLIN-4-YL-PROPYL)-BENZAMIDE

Step 1: 4-(Chloromethyl)benzoyl chloride (1.311 g, 6.93 mmol) was addedto the stirred solution of 3-morpholinopropan-1-amine (1 g, 6.93 mmol)in acetonitrile (20 mL) at room temperature. The resulting reactionsolution was stirred at room temperature for 2 hours and the reactionwas complete. The reaction mixture was diluted by EtOAc (50 mL) and thesolution was extracted with NaHCO₃ (aq. sat., 40 mL). The aqueous layerwas back extracted with EtOAc (2×20 mL). Organic layers were combinedand dried by MgSO₄. The mixture was filtered and concentrated to give4-chloromethyl-N-(3-morpholin-4-yl-propyl)-benzamide as a light redclear liquid (2.23 g, 117% crude yield) which was put to next stepwithout further purification: LCMS MH=297; ¹H NMR (DMSO-d₆) δ 1.68(quin, J=7.1 Hz, 2H, CH₂), 2.24-2.41 (m, 6H, CH₂, CH₂, CH₂), 3.19-3.39(m, 2H, CH₂), 3.48-3.64 (m, 4H, CH₂, CH₂), 4.81 (s, 2H, M₀₁), 7.52 (d,J=8.1 Hz, 2H, Ar), 7.83 (d, J=8.3 Hz, 2H, Ar), 8.51 (t, J=5.4 Hz, 1H,NH).

Step 2: DIPEA (0.359 ml, 2.053 mmol) was added to the stirred mixture ofmethyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (600mg, 2.053 mmol), 4-(chloromethyl)-N-(3-morpholinopropyl)benzamide (640mg, 2.155 mmol) and K₂CO₃ (284 mg, 2.053 mmol) in DMF (12 mL) at roomtemperature. The resulting mixture was reacted at 50° C. for 8 hours androom temperature for 2 days before it was added by K₂CO₃ (100 mg, 0.72mmol). The mixture was heated at 80° C. for 9 hours before the reactionstopped proceeding. The reaction mixture was filtered and the filtratewas diluted by dichloromethane (50 mL). The resulting solution wasextracted with brine (15 mL). The aqueous layer was back extracted withdichloromethane (25 mL). Organic layers were combined and dried withMgSO₄. The mixture was filtered and the filtrate was concentrated. Theresidue was purified by ISCO chromatography to give a clear solid (480mg), which was triturated in EtOAC (15 mL) and filtered to give4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-H-isoindol-4-yloxymethyl]-N-(3-morpholin-4-yl-propyl)-benzamide as a white solid (426 mg,82% yield): HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240nm, 15/85, (acetonitrile/0.1% H₃PO₄), 6.63 min (99.9%); mp: 160-162° C.;¹H NMR (DMSO-d₆) δ 1.67 (quin, J=7.0 Hz, 2H, CH₂), 1.93-2.06 (m, 1H,CH₂), 2.28-2.38 (m, 6H, CH₂, CH₂, CH₂), 2.39-2.47 (m, 1H, CHH),2.54-2.64 (m, 1H, CHH), 2.83-3.00 (m, 1H, CHH), 3.23-3.31 (m, 2H, CH₂),3.56 (t, J=4.7 Hz, 4H, CH₂, CH₂), 4.28 (d, J=17.6 Hz, 1H, CHH), 4.45 (d,J=17.6 Hz, 1H, CHH), 5.12 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.32 (s, 2H,CH₂), 7.32 (dd, J=7.6, 8.3 Hz, 2H, Ar), 7.48 (t, J=7.7 Hz, 1H, Ar), 7.56(d, J=8.1 Hz, 2H, Ar), 7.85 (d, J=8.3 Hz, 2H, Ar), 8.48 (t, J=5.5 Hz,1H, NH), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.34, 25.91, 31.18,37.71, 45.07, 51.58, 53.31, 56.02, 66.17, 68.98, 115.03, 115.35, 127.22,127.28, 129.78, 129.97, 133.34, 134.22, 139.60, 153.27, 165.76, 167.94,170.96, 172.81; LCMS MH=521; Anal. Calcd for C₂₈H₃₂N₄O₆+1.0H₂O: C,62.44; H, 6.36; N, 10.40; Found: C, 62.29; H, 6.41; N, 10.26.

5.1843-{4-[4-(ISOPROPYLAMINO-METHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To the acetonitrile solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 1.160 mmol), was added propan-2-amine (0.593 ml, 6.96 mmol)dropwise at room temperature. The mixture was stirred at roomtemperature overnight. The mixture was concentrated on rota-vap and theresulting oil was used in the next step directly.

Step 2: To the THF suspension of methyl5-amino-4-(4-(4-((isopropylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.45 g, 0.992 mmol), was added potassium tert-butoxide (0.223 g, 1.984mmol) at 0° C. The mixture was stirred for 5 minutes and quenched byadding 2 mL of 1N HCl followed by 10 mL of sat. NaHCO₃ and 20 mL ofCH₂Cl₂. The mixture was extracted and separated. The organic layer wasconcentrated on rota-vap and the resulting oil was stirred with ether(20 mL) to give3-{4-[4-(isopropylaminomethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a yellow solid (150 mg, 31%). mp: 165-167° C. HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1%H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R)=4.56 min (96%). ¹H NMR (DMSO-d₆) δ 0.98 (d, J=6.2 Hz, 6H, CH₃,CH₃), 1.88-2.05 (m, 1H, CHH), 2.35-2.48 (m, 1H, CHH), 2.53-2.62 (m, 1H,CHH), 2.63-2.74 (m, 1H, CH), 2.80-2.99 (m, 1H, CH), 3.68 (s, 2H, CH₂),4.15-4.51 (m, 2H, CH₂), 5.10 (dd, J=5.0, 13.1 Hz, 1H, NCH), 5.22 (s, 2H,CH₂), 7.24-7.62 (m, 7H, Ar), 11.00-11.10 (broad, 1H, NH). ¹³C NMR(DMSO-d₆) δ 22.37, 22.73, 31.21, 45.06, 47.08, 50.10, 51.57, 114.97,115.16, 127.55, 127.92, 129.76, 129.94, 133.30, 134.56, 141.36, 153.46,167.98, 171.08, 172.96. LCMS MH=422. Anal Calcd for C₂₄H₂₇N₃O₄+0.9H₂O:C, 65.86; H, 6.63; N, 9.60; Found: C, 66.02; H, 6.46; N, 9.25.

5.1853-[4-(4-CYCLOHEXYLAMINOMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the acetonitrile solution (10 mL) of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 1.160 mmol), was added cyclohexanamine (0.798 ml, 6.96 mmol)dropwise at room temperature. The mixture was stirred at roomtemperature overnight and was concentrated on rota-vap. The resultingmixture was used in the next step directly.

Step 2: To the THF solution (20 mL) of methyl5-amino-4-(4-(4-((cyclohexylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.4 g, 0.810 mmol), was added potassium 2-methylpropan-2-olate (0.136g, 1.216 mmol) at 0° C. The mixture was stirred at room temperature for5 minutes. The mixture was added 2 mL of 1N HCl followed by 10 mL ofsat. NaHCO₃ and 20 mL of CH₂Cl₂. The mixture was extracted andseparated. The organic layer was concentrated on rota-vap and theresulting solid was stirred with ether (20 mL) to give3-[4-(4-cyclohexylaminomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (250 mg, 47%). mp: 175-177° C. HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1%H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R)=4.80 min (95%). ¹H NMR (DMSO-d₆) δ 0.94-1.20 (m, 4H, CH₂, CH₂,CHH), 1.42-1.58 (m, 1H, CHH), 1.58-1.73 (m, 2H, CH₂), 1.80-1.84 (m, 2H,CH₂), 1.91-2.06 (m, 1H, CHH), 2.27-2.40 (m, 1H, CH), 2.40-2.48 (m, 1H,CHH), 2.53-2.64 (m, 1H, CHH), 2.79-3.04 (m, 1H, CHH), 3.71 (s, 2H, CH₂),4.10-4.60 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H,CH₂), 7.24-7.63 (m, 7H, Ar). ¹³C NMR (DMSO-d₆) δ 22.29, 24.34, 25.84,31.14, 32.81, 45.04, 49.51, 51.53, 55.05, 69.43, 114.94, 115.12, 127.51,127.83, 129.71, 129.90, 133.24, 134.50, 141.46, 153.43, 167.94, 170.90,172.75; LCMS MH=462. Anal Calcd for C₂₇H₃₁N₃O₄+0.4H₂O: C, 69.18; H,6.84; N, 8.96; Found: C, 69.02; H, 7.11; N, 8.79.

5.1863-(4-(4-((METHYL(2-MORPHOLINOETHYL)AMINO)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: To the acetonitrile solution (10 mL) of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 1.160 mmol), was added N-methyl-2-morpholinoethanamine (0.201 g,1.392 mmol) followed by DIPEA (0.243 ml, 1.392 mmol). The mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated and extracted with CH₂Cl₂ (30 mL) and water (30 mL).Organic layer was concentrated on rota-vap to give4-carbamoyl-4-[4-(4-{[methyl-(2-morpholin-4-yl-ethyl)-amino]-methyl}-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a foamy solid. It was used in the next step withoutfurther purification.

Step 2: To the THF solution (20 mL) of methyl5-amino-4-(4-(4-((methyl(2-morpholinoethyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.6 g, 1.114 mmol), was added potassium tert-butoxide (0.150 g, 1.337mmol). The mixture was stirred at 0° C. for 5 minutes. The reactionmixture was added 1N HCl (2 mL), followed by sat. NaHCO₃ (10 mL) andCH₂Cl₂ (30 mL). The mixture was extracted and separated. The organiclayer was dried over Na₂SO₄ and concentrated. The resulting foamy solidwas purified on silica gel column and eluted with CH₂Cl₂/MeOH to give3-(4-(4-((methyl(2-morpholinoethyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas white solid (0.34 g, 60%). mp: 193-195° C. HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1%H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R) 4.25 min (98%). ¹H NMR (DMSO-d₆) δ 1.94-2.05 (m, 1H, CHH), 2.14(s, 3H, CH₃), 2.30-2.38 (br. s., 4H, CH₂, CH₂), 2.38-2.49 (br. s., 5H,CH₂, CH₂, CHH), 2.54-2.60 (m., 1H, CHH), 2.89 (m, 1H, CHH), 3.43-3.63(m, 6H, CH₂, CH₂, CH₂), 4.22-4.45 (m, 2H, CH₂), 5.11 (dd, J=4.9, 13.2Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 7.31-7.51 (m, 6H, Ar), 10.97 (s, 1H,NH). ¹³C NMR (DMSO-d₆) δ 22.36, 31.21, 42.19, 45.10, 51.58, 53.63,53.88, 56.11, 61.43, 66.16, 69.44, 115.01, 115.23, 127.58, 128.77,129.79, 129.95, 133.31, 135.13, 139.01, 153.50, 168.01, 170.96, 172.83.Anal Calcd for C₂₈H₃₄N₄O₅+0.4H₂O: C, 65.45; H, 6.83; N, 10.90; Found: C,65.71; H, 7.11; N, 10.95.

5.1873-(4-{4-[(2-MORPHOLIN-4-YL-ETHYLAMINO)-METHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONEBIS HYDROCHLORIDE

Step 1: To a stirred solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.18 g, 2.75 mmol) in acetonitrile (15 ml), was added2-morpholinoethanamine (1.08 ml, 8.24 mmol). The reaction mixtureimmediately turned into a light green solution. The mixture was stirredat room temperature overnight and then evaporated to give a light greenoil, which was not further characterized and used in the next stepwithout purification.

Step 2: To a stirred solution of methyl5-amino-4-(4-(4-((2-morpholinoethylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.44 g, 2.75 mmol) in dichloromethane (15 ml), was added di-tert-butyldicarbonate (1.80 g, 8.25 mmol). The weight of the limiting SM wasassumed as 1.44 g, which was the theoretical yield of the previous step.The oil was purified on silica gel column (MeOH/CH₂Cl₂ gradient from 1%to 9% in 50 min) to give4-[4-(4-{[tert-butoxycarbonylmethyl-(2-morpholin-4-yl-ethyl)-amino]-methyl}-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as an oily solid (0.88 g, 51% yield over two steps).

Step 3: To a stirred solution of methyl5-amino-4-(4-(4-((tert-butoxycarbonyl(2-morpholinoethyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.36 g, 0.58 mmol) in THF (10 ml) at 0° C., was added potassium2-methylpropan-2-olate (0.07 g, 0.58 mmol). The reaction mixture wasstirred for ten minutes and was quenched with 1 N HCl (2 mL) to give aclear colorless solution. It was neutralized with saturated sodiumbicarbonate (4 ml to pH=8) to give a cloudy mixture, which was extractedwith ethyl acetate (2×20 mL). The ethyl acetate phase was concentratedand purified on silica gel column (MeOH/CH₂Cl₂ gradient from 1% to 5% in30 min) to give[{4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-(2-morpholin-4-yl-ethyl)-amino]-aceticacid tert-butyl ester as a foamy solid (0.21 g, 62% yield); HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄),5.38 min (97.4%); mp: 110-112° C.; ¹H NMR (DMSO-d₆) δ 1.29-1.49 (m, 9H,3CH₃), 1.92-2.05 (m, 1H, CHH), 2.25-2.39 (m, 6H, 3CH₂), 2.44 (dd, J=4.5,13.0 Hz, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.83-3.00 (m, 1H, CHH),3.15-3.29 (m, 2H, CH₂), 3.52 (t, J=4.6 Hz, 4H, 2CH₂), 4.19-4.49 (m, 4H,CH₂, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H, CH₂),7.23-7.37 (m, 4H, Ar), 7.41-7.53 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.36, 28.02, 31.21, 43.30, 45.09, 49.37, 50.05, 51.58,53.33, 55.95, 56.39, 66.17, 69.32, 78.84, 115.00, 115.23, 127.39,127.83, 129.78, 129.97, 133.31, 135.30, 138.56, 153.43, 155.02, 168.01,170.96, 172.83 (2 extra peaks in alkyl region possibly from the twoalkyl atoms close to the amide nitrogen atom due to the rotamer); LCMSMH=593; Anal. Calcd for C₃₂H₄₀N₄O₇+0.1H₂O: C, 64.65; H, 6.82; N, 9.42;Found: C, 64.31; H, 6.82; N, 9.24.

Step 4: To a stirred solution of tert-butyl4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl(2-morpholinoethyl)carbamate(0.27 g, 0.45 mmol) in dichloromethane (3 ml) was added 2M HCl/ether(2.5 ml). A white precipitate formed almost immediately. It was stirredat room temperature overnight and then filtered to give3-(4-{4-[(2-Morpholin-4-yl-ethylamino)-methyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionetwo hydrochloride as a yellow solid (176 mg, 74% yield); HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 05/95to 95/5 in 5 min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄),4.89 min (95.4%); mp: 258-260° C.; ¹H NMR (DMSO-d₆) δ 1.94-2.06 (m, 1H,CHH), 2.36-2.44 (m, 1H, CHH), 2.55-2.66 (m, 1H, CHH), 2.83-3.00 (m, 1H,CHH), 3.03-3.23 (m, 2H, CH₂), 3.47 (br. s., 6H, CH₂, CH₂, CH₂), 3.80(br. s., 2H, CH₂), 3.92-4.10 (m, 2H, CH₂), 4.15-4.51 (m, 4H, CH₂, CH₂),5.12 (dd, J=5.2, 13.1 Hz, 1H, NCH), 5.30 (s, 2H, CH₂), 7.27-7.38 (m, 2H,Ar), 7.44-7.52 (m, 1H, Ar), 7.53-7.65 (m, 4H, ArH), 9.43-9.67 (br.s,1.3H, NH or HCl), 10.97 (s, 1H, NH), 11.06-11.23 (br.s, 0.6H, NH orHCl); ¹³C NMR (DMSO-d₆) δ 22.36, 31.22, 40.67, 45.15, 49.89, 51.62,52.06, 54.93, 63.28, 69.03, 115.01, 115.33, 127.78, 129.81, 130.00,130.17, 131.44, 133.35, 137.48, 153.30, 167.98, 170.96, 172.85; LCMSMH=493; Anal. Calcd for C₂₇H₃₂N₄O₅.2 HCl: +1.1H₂O, +0.1 CH₂Cl₂: C,54.82; H, 6.18; N, 9.44; Cl, 13.13; Found: C, 54.56; H, 6.04; N, 9.31;Cl, 12.82.

5.1883-(4-{4-[(2-HYDROXY-ETHYLAMINO)-METHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: To a stirred solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.52 g, 1.21 mmol) in acetonitrile (10 ml) at room temperature, wereadded 2-aminoethanol (0.15 ml, 2.41 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.60 ml, 3.62 mmol). The reactionmixture was heated at 40° C. overnight and evaporated in vacuo to givean oil, which was mixed with methylene chloride (40 mL), washed withwater (3×20 mL) and evaporated to a clear oil (0.61 g, 111% crudeyield). It was used in the next step without further purification.

Step 2: To a stirred mixture of methyl5-amino-4-(4-(4-((2-hydroxyethylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.61 g, 1.34 mmol) in THF (15 ml) in an ice bath, was added potassium2-methylpropan-2-olate (0.65 g, 4.91 mmol), and the mixture was stirredfor ten minutes. The mixture was quickly quenched with 1N HCl (˜3 mL)and neutralized with saturated sodium bicarbonate (6 ml to pH=7), andthen extracted with methylene chloride (3×30 mL). The organic phaseswere combined, washed with brine (20 mL) and concentrated to anoff-white foamy solid (0.31 g, 54% yield). It was stirred in water (15mL) and extracted with methylene chloride (4×20 mL). The aqueous phasewas quickly frozen by acetone/dry ice mixture and lyophilized overnight.The weight of the white fluffy solid after lyophilizing was 83 mg. Itwas mixed with methylene chloride (2 mL, partially dissolved), added 2MHCl/ether (1.2 mL, 6 eq) and stirred overnight. The suspension wasfiltered and rinsed with diethyl ether. The filtered off-white solid wasdried in vacuum oven to give3-(4-{4-[(2-hydroxy-ethylamino)-methyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione(57 mg, 10% yield over two steps); HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5 min,isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄), 5.13 min (92.2%);mp: 251-253° C.; ¹H NMR (DMSO-d₆) δ 1.92-2.06 (m, 1H, CHH), 2.37-2.47(m, 1H, CHH), 2.54-2.65 (m, 1H, CHH), 2.83-3.00 (m, 3H, CH₂, CHH), 3.68(t, J=5.4 Hz, 2H, CH₂), 4.11-4.20 (m, 2H, CH₂), 4.23-4.50 (m, 2H, CH₂),5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.29 (s, 2H, CH₂), 7.29-7.37 (m, 2H,Ar), 7.43-7.64 (m, 5H, Ar), 9.18-9.41 (m, 2H, HClNH), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.36, 31.21, 45.13, 48.40, 49.49, 51.62, 56.30,69.07, 115.01, 115.32, 127.74, 129.81, 130.00, 130.33, 131.65, 133.35,137.30, 153.34, 167.98, 170.98, 172.85; LCMS MH=424; Anal Calcd forC₂₃H₂₅N₃O₅.HCl: C, 60.06; H, 5.70; N, 9.14; Cl, 7.71. Found: C, 48.95;H, 5.00; N, 7.28; Cl, 14.92.

5.189 4-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YLOXY)METHYL)-N-(2-HYDROXY-2METHYLPROPYL)BENZAMIDE

To a solution of 4-(chloromethyl)-N-(2-hydroxy-2-methylpropyl)benzamide(0.73 g, 3.02 mmol) and methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.839 g,2.87 mmol) in DMF (10 mL), was added DIEA (0.527 ml, 3.02 mmol) at roomtemperature. The mixture was stirred at room temperature overnight. Thesolution was heated to 40° C. To the mixture was added K₂CO₃ (0.417 g,3.02 mmol). The mixture was stirred at room temperature for 4 days. Thereaction mixture was heated to 35° C. for 1 day. The mixture was heatedto 80° C. overnight. The mixture was cooled to room temperature. Thesuspension was filtered and washed with acetonitrile (15 mL). Thefiltrate was acidified with HCOOH (2 mL). The solution was purified withprep HPLC, (Xbridge C18, 10 μm, 50×250 mm, 143 mL/min, 240 nM, 2/98/2min, gradient to 95/5 acetonitrile 0.1% FA/H2O 0.1% formic acid in 30min) to give4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)-N-(2-hydroxy-2-methylpropyl)benzamideas a white solid (0.18 g, 12.8% yield): HPLC: (Waters Symmetry C18, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 acetonitrile/0.1% H3PO4) 4.72(95.2%); mp: 165-167° C.; 1H NMR (DMSO-d6) δ 1.10 (s, 6H, CH3, CH3),1.87-2.11 (m, 1H, CHH), 2.36-2.47 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH),2.77-3.04 (m, 1H, CHH), 3.25 (d, J=6.0 Hz, 2H, CH2), 4.31 (s, 1H, CHH),4.42 (s, 1H, CHH), 4.55 (s, 1H, OH), 5.00-5.20 (m, 1H, NCH), 5.33 (s,2H, CH2), 7.33 (dd, J=5.7, 7.0 Hz, 2H, Ar), 7.48 (t, J=7.7 Hz, 1H, Ar),7.57 (d, J=8.3 Hz, 2H, Ar), 7.88 (d, J=8.3 Hz, 2H, Ar), 8.24 (t, J=6.1Hz, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.27, 27.28, 31.11,45.01, 50.12, 51.52, 68.92, 69.72, 114.96, 115.28, 127.15, 127.40,129.73, 129.92, 133.28, 134.27, 139.59, 153.21, 166.30, 167.87, 170.89,172.74; LCMS MH=466; Anal. Calcd for C₂₅H₂₇N₃O₆+1 H2O: C, 62.10; H,6.05; N, 8.69; Found: C, 62.00; H, 5.74; N, 8.65.

5.1903-(4-{4-[(DIISOPROPYLAMINO)-METHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: To a stirred colorless solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.00 g, 2.32 mmol) in acetonitrile (10 ml) at room temperature, wasadded diisopropylamine (2.95 ml, 20.88 mmol). The mixture was stirred at100° C. for two days. The reaction could not go completed and themixture was used in the next step by a solvent swap to DMF without anypurification.

Step 2: A mixture of methyl5-amino-4-(4-(4-((diisopropylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(1.15 g, 2.32 mmol) and potasium carbonate (0.32 g, 2.32 mmol) in DMF(15 ml) was heated at 80° C. overnight. The suspension was filtered andrinsed with DMF to give a brown filtrate and off-white solid. Thefiltrate was evaporated to an oil and purified on silica gel column(MeOH/CH₂Cl₂ gradient from 1% to 9% in 50 min) to give3-(4-{4-[(Diisopropylamino)-methyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (38 mg, 7% yield); HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5 min,isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄), 5.35 min (95.8%);mp: 201-203° C.; ¹H NMR (DMSO-d₆) δ 0.98 (d, J=6.6 Hz, 12H, 4CH₃),1.90-2.05 (m, 1H, CHH), 2.35-2.46 (m, 1H, CHH), 2.53-2.65 (m, 2H, CHH,CHH), 2.82-3.05 (m, 2H, CHH, CHH), 3.61 (s, 2H, CH₂), 4.18-4.49 (m, 2H,CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.20 (s, 2H, CH₂), 7.26-7.55(m, 7H, Ar), 10.96 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.60, 22.35, 31.21,45.10, 47.35, 48.03, 51.58, 69.52, 114.95, 115.19, 127.56, 127.64,129.81, 129.95, 133.29, 134.39, 142.81, 153.56, 168.02, 170.96, 172.83;LCMS MH=464; Anal. Calcd for C₂₇H₃₃N₃O₄+1.1H₂O: C, 67.09; H, 7.34; N,8.69. Found: C, 66.73; H, 6.99; N, 8.56.

5.1913-(1-OXO-4-{4-[(TETRAHYDRO-PYRAN-4-YLAMINO)-METHYL]-BENZYLOXY}-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: To a solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 1.16 mmol) in THF (10 mL), was added tetrahydro-2H-pyran-4-amine(0.29 g, 2.90 mmol) at room temperature. The mixture was stirred at roomtemperature overnight and then heated at 45° C. for three hours. Thereaction mixture was filtered to get rid of the solid. The filtrate wasconcentrated and extracted with water and dichloromethane. The organiclayer was concentrated to give a yellow foamy solid (0.50 g, 87% yield),which was purified on silica gel (MeOH/CH₂Cl₂ gradient from 1% to 10% in30 min) to give4-carbamoyl-4-(1-oxo-4-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-butyricacid methyl ester as an oil (0.40 g, 70% yield). It was used in the nextstep without further purification.

Step 2: To a stirred solution of methyl5-amino-5-oxo-4-(1-oxo-4-(4-((tetrahydro-2H-pyran-4-ylamino)methyl)benzyloxy)isoindolin-2-yl)pentanoate(0.40 g, 0.81 mmol) in THF (15 ml) in an ice bath, was added potassium2-methylpropan-2-olate (0.10 g, 0.90 mmol). The mixture was stirred forten minutes and then quenched with 1N HCl (2 ml) and neutralized withsaturated sodium bicarbonate (3 ml to pH=7). The mixture was stirredwith ethyl acetate (30 ml) and separated. The organic phase was washedwith brine (20 ml) and concentrated to an off-white solid, which waspurified on silica gel column (MeOH/CH₂Cl₂ gradient from 1% to 10% in 30min) to give3-(1-oxo-4-{4-[(tetrahydro-pyran-4-ylamino)-methyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (80.8 mg, 22% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 jpm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄), 4.89 min(98.7%); mp: 231-233° C.; ¹H NMR (DMSO-d₆) δ 1.19-1.32 (m, 3H, NH, CH₂),1.74-1.79 (m, 2H, CH₂), 1.96-2.00 (m, 1H, CHH), 2.37-2.47 (m, 1H, CHH),2.51-2.60 (m, 2H, 2CH), 2.85-2.97 (m, 1H, CHH), 3.20-3.28 (m, 2H, CH₂),3.73 (s, 2H, CH₂), 3.78-3.84 (m, 2H, CH₂), 4.22-4.44 (m, 2H, CH₂), 5.11(dd, J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.31-7.51 (m, 7H, Ar),10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.32, 31.17, 33.10, 45.08,49.08, 51.56, 52.36, 65.76, 69.45, 115.00, 115.18, 127.57, 127.94,129.77, 129.95, 133.28, 134.64, 141.20, 153.46, 167.99, 170.95, 172.81;LCMS MH=464; Anal. Calcd for C₂₆H₂₉N₃O₅ (0.5H₂O): C, 66.09; H, 6.40; N,8.89. Found: C, 65.90; H, 6.21; N, 8.62.

5.1924-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-N-(3-PIPERIDIN-1-YL-PROPYL)-BENZAMIDE

Step 1: 3-(Piperidin-1-yl)propan-1-amine (411 mg, 2.89 mmol) was addedto a stirred solution of 4-(chloromethyl)benzoyl chloride (546 mg, 2.89mmol) in acetonitrile (10 mL) through syringe. After addition thesolution was stirred at room temperature for 20 minutes and the reactionwas complete. The reaction mixture was added by NaHCO₃ (aq. sat., 20mL). The clear solution was back extracted with EtOAc (3×25 mL). Organiclayers were combined and dried by MgSO₄. The mixture was filtered andconcentrated under vacuo to give4-chloromethyl-N-(3-piperidin-1-yl-propyl)-benzamide as a light brownoil (700 mg, 82%). The compound was used in the next step as is: ¹H NMR(DMSO-d₆) δ 1.37 (d, J=5.1 Hz, 2H, CH₂), 1.42-1.54 (m, 4H, CH₂, CH₂),1.66 (t, J=7.0 Hz, 2H, CH₂), 2.23-2.39 (m, 6H, CH₂, CH₂, CH₂), 3.19-3.31(m, 2H, CH₂), 4.80 (s, 2H, CH₂), 7.51 (d, J=8.1 Hz, 2H, Ar), 7.83 (d,J=8.1 Hz, 2H, Ar), 8.53 (t, J=5.4 Hz, 1H, NH); LCMS MH=295.

Step 2: To the mixture of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (694 mg,2.374 mmol), 4-(chloromethyl)-N-(3-(piperidin-1-yl)propyl)benzamide (700mg, 2.374 mmol) and K₂CO₃ (328 mg, 2.374 mmol), was added DMF (10 mL).The reaction mixture was stirred at 50° C. overnight and K₂CO₃ (150 mg,1.08 mmol) was added. The resulting mixture was heated at 80° C. for 2hours. The reaction mixture was acidified by HCl (1N, aq. 8 mL) followedby addition of NaHCO₃ (aq. sat. 8 mL) and brine (10 mL). The aqueouslayer was back extracted with dichloromethane (3×35 mL). The organiclayers were combined and dried by MgSO₄. The mixture was filtered andconcentrated. The residue was purified by ISCO chromatography to give awhite solid. The solid was triturated in dichloromethane (1 mL) andether (15 mL) to give4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-N-(3-piperidin-1-yl-propyl)-benzamideas a white solid (84 mg, 6.8% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 18/82, (acetonitrile/0.1% H₃PO₄),4.54 min (98.5%); mp: 183-185° C.; ¹H NMR (DMSO-d₆) δ 1.37 (d, J=5.1 Hz,2H, CH₂), 1.43-1.54 (m, 4H, CH₂, CH₂), 1.67 (quin, J=7.0 Hz, 2H, CH₂),1.93-2.07 (m, 1H, CHH), 2.31 (d, J=5.7 Hz, 5H, CH₂, CH₂), 2.40-2.47 (m,1H, CHH), 2.53-2.66 (m, 1H, CHH), 2.83-3.01 (m, 1H, CHH), 3.21-3.37 (m,3H, CH₂, CHH), 4.28 (d, J=17.6 Hz, 1H, CHH), 4.45 (d, J=17.4 Hz, 1H,CHH), 5.12 (dd, J=5.0, 13.1 Hz, 1H, CHH), 5.32 (s, 2H, CH₂), 7.32 (dd,J=7.6, 8.3 Hz, 2H, Ar), 7.48 (t, J=7.7 Hz, 1H, Ar), 7.56 (d, J=8.3 Hz,2H, Ar), 7.84 (d, J=8.1 Hz, 2H, Ar), 8.50 (t, J=5.4 Hz, 1H, NH), 10.98(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.34, 24.05, 25.52, 26.19, 31.18,37.97, 45.07, 51.59, 54.01, 56.43, 68.98, 115.03, 115.35, 127.25,127.21, 129.78, 129.97, 133.34, 134.29, 139.58, 153.29, 165.73, 167.91,170.96, 172.81; LCMS MH=519; Anal. Calcd for C₂₉H₃₄N₄O₅+0.4H₂O: C,66.24; H, 6.67; N, 10.66; Found: C, 66.17; H, 6.43; N, 10.53.

5.1932-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYLAMINO}-2-METHYL-PROPIONIC ACID

Step 1:4-(4-{4-[(1-tert-Butoxycarbonyl-1-methyl-ethylamino)-methyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl-butyricacid methyl ester

To the stirred solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(600 mg, 1.262 mmol) in Acetonitrile (10 mL) at room temperature wasadded by tert-butyl 2-amino-2-methylpropanoate hydrochloride (272 mg,1.389 mmol) and DIPEA (0.551 ml, 3.16 mmol). The reaction was stirred atroom temperature over night for 5 days and added by EtOAc(50 mL), NaHCO₃(aq, sat, 5 mL) and brine (15 mL). The mixture was extracted and organiclayer was concentrated in vacuo. The residue was purified by ISCOchromatography to give4-(4-{4-[(1-tert-Butoxycarbonyl-1-methyl-ethylamino)-methyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl-butyricacid methyl ester as a clear sticky solid (470 mg, 67% yield); LCMSMH=554; ¹H NMR (DMSO-d₆) δ 1.21 (s, 6H, CH₃, CH₃), 1.44 (s, 9H, CH₃,CH₃, CH₃), 1.97-2.32 (m, 4H, CH₂, CH₂, CH), 3.50 (s, 3H, CH₃), 3.58 (d,J=5.7 Hz, 2H, CH₂), 4.39 (d, J=17.6 Hz, 1H, CHH), 4.52 (d, J=17.6 Hz,1H, CHH), 4.72 (dd, J=4.6, 10.1 Hz, 1H, CHH), 5.22 (s, 2H, CH₂), 7.18(s, 1H, NHH), 7.25-7.32 (m, 2H, Ar), 7.32-7.39 (m, 2H, Ar), 7.40-7.49(m, 3H, Ar), 7.58 (s, 1H, NHH).

Step 2:2-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzylamino}-2-methyl-propionic acid tert-butyl ester

To the stirred solution of methyl5-amino-4-(4-(4-((1-tert-butoxy-2-methyl-1-oxopropan-2-ylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(470 mg, 0.849 mmol) in Tetrahydrofuran (Volume: 10 ml) at 0° C. wasadded by potassium tert-butoxide (95 mg, 0.849 mmol) in one portion. Themixture was stirred at 0° C. for 15 mins. The reaction mixture wasdiluted by EtOAc (50 mL) and quenched by HCl (1N, aq, 3 mL) followed bythe addition of NaHCO₃ (aq, sat., 3 mL) and brine (15 mL). The mixturewas extracted and the organic layer was dried by MgSO₄. The mixture wasfiltered and concentrated in vacuo to give2-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzylamino}-2-methyl-propionicacid tert-butyl ester as a white solid (460 mg, 104% crude yield). Thecompound was used in the next step without further purification; LCMSMH=522.

Step 3:2-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzylamino}-2-methyl-propionic acid

To the suspension of tert-butyl2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzylamino)-2-methylpropanoate(360 mg, 0.690 mmol) in DCM (2 mL) was added hydrogen chloride, 2M inether (8 ml, 16.00 mmol). The resulting suspension was stirred at roomtemperature for 5 days before it was concentrated under vacuo. Theresidue was purified by prepHPLC to give2-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzylamino}-2-methyl-propionicacid as a white solid (125 mg, 39%); HPLC: Waters Symmetry C-18, 3.9×150mm, 5 μm, 1 mL/min, 240 nm, 5-95% in 10 mins, (CH₃CN/0.1% H₃PO₄), 5.96min (98.4%); mp: 271-272° C.; ¹H NMR (DMSO-d₆) δ 1.32 (s, 6H, CH₃, CH₃),1.93-2.05 (m, 1H, CHH), 2.35-2.48 (m, 1H, CHH), 2.54-2.64 (m, 1H, CHH),2.88 (d, J=18.5 Hz, 1H, CHH), 3.89 (s, 2H, CH₂), 4.25 (d, J=17.6 Hz, 1H,CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CHH),5.27 (s, 2H, CH₂), 7.26-7.37 (m, 2H, Ar), 7.40-7.58 (m, 5H, Ar), 10.98(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 23.26, 23.33, 31.18, 45.07,46.38, 51.58, 61.65, 69.26, 115.16, 115.29, 127.66, 129.41, 129.77,130.03, 133.30, 135.37, 136.33, 153.33, 167.97, 170.99, 172.81, 173.07;LCMS MH=466; Anal. Calcd for C₂₅H₂₇N₃O₆+1.9H₂O: C, 60.09; H, 6.21; N,8.41; Found: C, 60.01; H, 5.98; N, 8.23.

5.1943-(4-(4-((METHYL(TETRAHYDRO-2H-PYRAN-4-YL)AMINO)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONEFORMATE

(3-(4-(4-(Bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(150 mg, 0.338 mmol)) was slurried in MeCN (5 mL).N-methyltetrahydro-2H-pyran-4-amine (136 mg, 1.184 mmol) was added tothe mixture and the resulting mixture was stirred at room temperaturefor ˜15 min. The reaction mixture was diluted with EtOAc (100 mL) and 1NNaHCO₃ (30 mL). The cloudy organic layer was concentrated in vacuo andthe remaining residue was triturated with water (100 mL) and Et₂O (˜100mL). The solid was collected by filtration and suction dried on filterfunnel and then placed in vacuum oven at 40° C. overnight to give 125 mgof white solid. The solid was dissolved in DMF/1 N HCl (12 mL/1 mL) andpurified by injection onto a C-18 preparatory HPLC column. The productwas eluted with an acetonitrile/water gradient (0.1% formic acid in bothmobile phases, 5% to 50% MeCN over 20 minutes) and fractions werecollected by mass trigger. The desired fractions were combined andconcentrated in vacuo to give3-(4-(4-((methyl(tetrahydro-2H-pyran-4-yl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneFormate as a white solid (25 mg, 15% yield) as a white solid: HPLC:Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 17/83CH₃CN/0.1% H₃PO₄, 4.48 min (98.1%); ¹H NMR (DMSO-d₆) δ 1.43-1.59 (m, 2H,CHH, CHH), 1.62-1.76 (m, 2H, CHH, CHH), 1.92-2.04 (m, 1H, CHH), 2.09 (s,3H, CH₃), 2.35-2.48 (m, 1H, CHH), 2.52-2.71 (m, 2H, CHH, CH), 2.82-2.99(m, 1H, CHH), 3.18-3.32 (m, 2H, CHH, CHH), 3.55 (s, 2H, CH₂), 3.90 (dd,J=3.8, 11.1 Hz, 2H, CHH, CHH), 4.25 (d, J=17.6 Hz, 1H, CHH), 4.42 (d,J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.2, 13.1 Hz, 1H, CH), 5.22 (s, 2H,CH₂), 7.26-7.37 (m, 4H, Ar), 7.37-7.55 (m, 3H, Ar), 10.96 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.33, 28.89, 31.18, 37.14, 45.07, 51.55, 56.77,59.08, 66.61, 69.45, 114.99, 115.19, 127.60, 128.47, 129.78, 129.95,133.28, 134.92, 139.93, 153.49, 167.99, 170.96, 172.81; LC/MS M+H=478.

5.1953-{4-[4-(TERT-BUTYLAMINO-METHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: Preparation of4-{4-[4-(tert-Butylamino-methyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester

To a stirred solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.611 g, 1.285 mmol) in acetonitrile (15 ml) was added2-methylpropan-2-amine (0.406 ml, 3.86 mmol). The mixture was stirredfor six hours and then solvent was evaporated to give an oil, which wasstirred in water (20 ml) and methylene chloride (30 ml). The resultingwhite suspension was filtered to give4-{4-[4-(tert-Butylamino-methyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester as a white solid (0.523 g, 87% yield); ¹H NMR(DMSO-d₆) δ 1.37 (s, 9H, 3CH₃), 1.97-2.34 (m, 4H, CH₂, CH₂), 3.50 (s,3H, CH₃), 4.06-4.22 (m, 2H, CH₂), 4.35-4.61 (m, 2H, CH₂), 4.74 (dd,J=5.0, 10.3 Hz, 1H, NCH), 5.24-5.37 (m, 2H, CH₂), 7.19 (br. s., 1H,NHH), 7.25-7.35 (m, 2H, Ar), 7.41-7.50 (m, 1H, Ar), 7.52-7.70 (m, 5H,NHH, Ar), 8.61 (br. s., 2H, NHHCl); ¹³C NMR (DMSO-d₆) δ 24.96, 25.17,30.36, 44.32, 44.77, 51.30, 53.40, 56.96, 69.01, 114.72, 115.24, 127.99,129.59, 130.26, 132.17, 133.48, 137.55, 153.22, 167.80, 171.75, 172.51.It was used in the next step without further purification.

Step 2: Preparation of3-{4-[4-(tert-Butylamino-methyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To a stirred solution of methyl5-amino-4-(4-(4-((tert-butylamino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 1.069 mmol) in THF (20 ml) in an ice-bath was added potassium2-methylpropan-2-olate (0.240 g, 2.14 mmol). The mixture was stirred forten minutes and 1N HCl (3 ml) was added and neutralized by saturatedsodium bicarbonate (6 ml) to pH=7. Ethyl acetate (50 ml) was added tothe mixture and stirred for 5 min. The organic phase was separated,washed with brine (10 ml) and evaporated to a white foamy solid (0.38g). It was stirred in ether (20 ml) for one hour then filtered to give3-{4-[4-(tert-Butylamino-methyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.279 g, 60% yield); mp 194-196° C.; HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 4.42min (95.4%); ¹H NMR (DMSO-d₆) δ 1.04-1.21 (m, 9H, 3CH₃), 1.92-2.06 (m,1H, CHH), 2.36-2.48 (m, 1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.83-2.99 (m,1H, CHH), 3.68 (br. s., 2H, CH₂), 4.18-4.47 (m, 2H, CH₂), 5.11 (dd,J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.27-7.53 (m, 7H, Ar),10.88-11.20 (weak, OH, NH); ¹³C NMR (DMSO-d₆) δ 22.36, 28.62, 31.21,45.10, 45.88, 51.59, 69.45, 115.04, 115.19, 127.55, 128.19, 129.78,129.97, 133.31, 134.69, 153.46, 168.01, 170.96, 172.82; LC/MS(M+1)⁺=436; Anal Calcd for C₂₅H₂₉N₃O₄+0.2H₂O: C, 68.38; H, 6.75; N,9.57. Found: C, 68.16; H, 6.62; N, 9.52.

5.1963-{1-OXO-4-[4-(PIPERAZINE-1-CARBONYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONEHYDROCHLORIDE

Step 1: To a stirred solution of 4-(chloromethyl)benzoyl chloride (1.890g, 10 mmol) in MeCN (30 mL) at room temperature, was added tert-butylpiperazine-1-carboxylate (1.9 g, 10.20 mmol) and N-methylmorpholine (1.1ml, 10.01 mmol). The mixture was stirred for 5 min. The reaction mixturewas stored at −20° C. overnight during which a solid formed. The mixturewas diluted with equal volume of water (about 30 mL) and the solid wascollected by suction filtration and washed with another portion of water(about 20 mL). The remaining solid on the filter was dried in vacuumoven to give a white solid (1.93 g). A second crop of solid formed inthe combined filtrate/wash and was collected by filtration and dried togive 4-(4-chloromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butylester as a white solid (917 mg, 27% yield). LCMS analysis indicated thatthe second crop was of higher purity and was used in the next stepwithout further purification. ¹H NMR (DMSO-d₆) δ 1.41 (s, 9H, tBu),3.11-3.72 (m, 8H, 4×CH₂), 4.80 (s, 2H, CH₂), 7.42 (d, J=8.3 Hz, 2H, Ar),7.51 (d, J=8.1 Hz, 2H, Ar); ¹³C NMR (DMSO-d₆) δ 27.97, 43.35, 45.48,79.15, 127.32, 128.81, 135.56, 139.00, 153.76, 168.70; LCMS: MH=339,341.

Step 2: To a solution of methyl5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.400 g,1.369 mmol) in DMF (5.01 mL), was added DIEA (0.239 ml, 1.369 mmol), andpotassium carbonate (0.189 g, 1.369 mmol). After stirring atroomtemperature for about 5 min,4-(4-chloromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester(0.455 g, 1.342 mmol) was added and the mixture was stirred at roomtemperature overnight. After about 17 h, the mixture was warmed to 50°C. for 3 h and then 60° C. for 22 h. The mixture was heated further to80° C. for about 24 h. The crude mixture was transferred to a beakerwith a 10% solution of AcOH in H₂O (50 mL). Immediately, a white solidformed upon transfer. The slurry was vigorously stirred and sonicatedfor 5 minutes then filtered on a medium pore fritted filter funnel. Thesolid was washed with copious water (total filtrate volume about 220 mL)and suction dried to give an off-white solid which was purified bysilica gel flash chromatography (80 μm ISCO column, eluted with a MeCNin DCM gradient) to give4-{4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl-oxymethyl]-benzoyl}-piperazine-1-carboxylicacid tert-butyl ester as a white solid (350 mg, 46% yield). LCMS:MH=563. The solid was used in the next step without furtherpurification.

Step 3: To a stirred solution of4-{4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl-oxymethyl]-benzoyl}-piperazine-1-carboxylicacid tert-butyl (350 mg, 0.622 mmol) in DCM (3 mL) atroom temperature,was added HCl (2 mL, 4.00 mmol, 2 N in Et₂O). The mixture becameincreasingly cloudy with significant solid forming. The thick slurry wasbriefly sonicated and then stirred atroom temperature for 26 h. Theslurry was diluted with Et₂O (˜40 mL) and then filtered. The collectedwhite solid was suction dried and then washed on filter funnel withEtOAc (50 mL) followed by MeCN (˜50 mL). The remaining solid was suctiondried on filter funnel, then dried in vacuum oven to give3-{1-oxo-4-[4-(piperazine-1-carbonyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dionehydrochloride as a white solid (300 mg, 97% yield): HPLC:Waters SymmetryC₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 4.73min (96.7%); mp: 285-287° C.; ¹H NMR (DMSO-d₆) δ 1.92-2.05 (m, 1H, CHH),2.33-2.46 (m, 1H, CHH), 2.54-2.65 (m, 1H, CHH), 2.83-3.02 (m, 1H, CHH),3.02-3.24 (m, 4H, CH₂, CH₂), 3.50-4.03 (m, 4H, CH₂, CH₂), 4.28 (d,J=17.6 Hz, 1H, CHH), 4.45 (d, J=17.6 Hz, 1H, CHH), 5.13 (dd, J=5.0, 13.3Hz, 1H, CH), 5.32 (s, 2H, CH₂), 7.21-7.39 (m, 2H, Ar), 7.42-7.62 (m, 5H,Ar), 9.11 (br. s., 2H, NH₂ salt), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ24.11, 32.89, 46.57, 47.35, 53.72, 70.93, 117.11, 117.41, 128.97,129.46, 131.79, 132.02, 134.89, 137.07, 139.91, 155.13, 171.08, 172.79,175.11, 179.00; LCMS: MH=463; Anal Calcd for C₂₅H₂₆N₄O₅.HCl+0.6H₂O: C,58.90; H, 5.58; N, 10.99; Found: C, 58.91; H, 5.58; N, 10.78.

5.1973-{4-[4-(MORPHOLINE-4-SULFONYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: 4-(4-Bromomethyl-benzenesulfonyl)-morpholine

To the stirred solution of morpholine (0.30 ml, 3.4 mmol) andTRIETHYLAMINE (0.53 ml, 3.8 mmol) in ether (5 mL) at 0° C. was addedsolution of 4-(bromomethyl)benzene-1-sulfonyl chloride (0.928 g, 3.4mmol) in ether (5 mL) drop wise. The resulting suspension was stirred atroom temperature for 17.5 hrs before it was dissolved in acetonitrile(80 mL) and EtOAC (20 mL). The mixture was washed with brine (20 mL).Organic layer was dried by MgSO₄ and concentrated under vacuo. Theresidue was purified by ISCO to give4-(4-Bromomethyl-benzenesulfonyl)-morpholine as a white solid (800 mg,73%). The compound was put to next step without further purification. ¹HNMR (DMSO-d₆) δ 2.77-2.94 (m, 4H, CH₂, CH₂), 3.54-3.70 (m, 4H, CH₂,CH₂), 4.81 (s, 2H, CH₂), 7.74 (s, 4H, Ar); LCMS MH=320, 322.

Step 2:4-Carbamoyl-4-{4-[4-(morpholine-4-sulfonyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester

Methyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (350mg, 1.2 mmol), 4-(4-(bromomethyl)phenylsulfonyl)morpholine (498 mg, 1.6mmol) and K₂CO₃ (165 mg, 1.2 mmol) were mixed in Acetonitrile (15 mL) atroom temperature. The resulting mixture was stirred at 50° C. for 16 hrsand K₂CO₃ (15 mg, 0.1 mmol) was added. The reaction mixture was stirredat 50° C. for 3.5 hrs. The reaction mixture was filtered and the solidwas washed with DCM (2×20 mL). The filtrate was concentrated and theresidue was purified by ISCO to give4-Carbamoyl-4-{4-[4-(morpholine-4-sulfonyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a white solid (560 mg, 88% yield); ¹H NMR (DMSO-d₆)δ 2.01-2.33 (m, 4H, CH₂, CH₂), 2.82-2.93 (m, 4H, CH₂, CH₂), 3.50 (s, 3H,CH₃), 3.59-3.68 (m, 4H, CH₂, CH₂), 4.47 (d, J=17.8 Hz, 1H, CHH), 4.60(d, J=17.6 Hz, 1H, CHH), 4.75 (dd, J=4.7, 10.2 Hz, 1H, CHH), 5.41 (s,2H, CH₂), 7.20 (s, 1H, NHH), 7.26-7.36 (m, 2H, Ar), 7.42-7.52 (m, 1H,Ar), 7.60 (s, 1H, NHH), 7.79 (s, 4H, Ar); LCMS MH=532.

Step 3:3-{4-[4-(Morpholine-4-sulfonyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred suspension of methyl5-amino-4-(4-(4-(morpholinosulfonyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (560 mg, 1.1 mmol) inTetrahydrofuran (15 mL) at 0° C. was added POTASSIUM TERT-BUTOXIDE (130mg, 1.2 mmol). The reaction mixture was stirred for 1 hr and POTASSIUMTERT-BUTOXIDE (30 mg, 0.28 mmol) was added. The reaction mixture wasstirred at 0° C. for 15 mins and then added by MeOH (20 mL) followed bythe addition of HCl (aq, 1N, 5 mL). The mixture was added by brine (15mL) and EtOAc (25 mL). The mixture was filtered and the filtrate wasconcentrated until solid started to precipitate out. The mixture wasfiltered and the solid was purified by stirred in mixed solvents of MeOH(5 mL), DCM (15 mL) and EtOAc (15 mL) to give3-{4-[4-(Morpholine-4-sulfonyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (209 mg, 39% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 35/65, (CH₃CN/0.1% H₃PO₄), 5.06 min(95.4%); mp: 308-310° C.; ¹H NMR (DMSO-d₆) δ 1.93-2.09 (m, 1H, CHH),2.35-2.47 (m, 1H, CHH), 2.54-2.67 (m, 1H, CHH), 2.80-3.03 (m, 5H, CHH,CH₂, CH₂), 3.55-3.69 (m, 4H, CH₂, CH₂), 4.32 (d, J=17.6 Hz, 1H, CHH),4.48 (d, J=17.4 Hz, 1H, CHH), 5.13 (dd, J=4.9, 13.2 Hz, 1H, CHH), 5.41(s, 2H, CH₂), 7.34 (dd, J=7.7, 10.0 Hz, 2H, Ar), 7.43-7.56 (m, 1H, Ar),7.78 (s, 4H, Ar), 10.99 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.39, 31.16,45.01, 45.85, 51.56, 65.22, 68.55, 114.97, 115.54, 127.87, 128.04,129.87, 129.96, 133.40, 133.82, 142.44, 153.19, 167.91, 170.96, 172.83;LCMS MH=500; Anal. Calcd for C₂₄H₂₅N₃O₇S+.5H₂O: C, 56.68; H, 5.15; N,8.26; Found: C, 56.71; H, 5.00; N, 8.16.

5.1983-{4-[4-(4-ISOPROPYL-PIPERIDINE-1-SULFONYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: 1-(4-Bromomethyl-benzenesulfonyl)-4-isopropyl-piperidine

To the stirred solution of 4-isopropylpiperidine (0.22 g, 1.7 mmol) andTRIETHYL AMINE (0.26 ml, 1.9 mmol) in ether (5 mL) at 0° C. was addedsolution of 4-(bromomethyl)benzene-1-sulfonyl chloride (0.466 g, 1.7mmol) in ether (5 mL) drop wise. After addition the reaction mixture wasstirred at 0° C. for 3 hrs. The reaction mixture was washed with water(15 mL) and brine (20 mL). Organic layer was dried by MgSO₄ andconcentrated under vacuo to give1-(4-Bromomethyl-benzenesulfonyl)-4-isopropyl-piperidine as a whitesolid (580 mg, 93% yield). The compound was put to next step withoutfurther purification. ¹H NMR (DMSO-d₆) δ 0.78 (d, J=6.8 Hz, 6H, CH₃,CH₃), 0.89-1.04 (m, 1H, CH), 1.06-1.25 (m, 2H, CH₂), 1.28-1.46 (m, 1H,CH), 1.55-1.73 (m, 2H, CH₂), 2.16 (td, J=2.2, 11.9 Hz, 2H, CH₂), 3.68(d, J=11.7 Hz, 2H, CH₂), 4.79 (s, 2H, CH₂), 7.71 (d, J=2.6 Hz, 4H, Ar);LCMS MH=360, 362.

Step 2:4-Carbamoyl-4-{4-[4-(4-isopropyl-piperidine-1-sulfonyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester Methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (360 mg, 1.2mmol), I-(4-(bromomethyl)phenylsulfonyl)-4-isopropylpiperidine (577 mg,1.6 mmol) and POTASSIUM CARBONATE (187 mg, 1.4 mmol) were mixed inAcetonitrile (15 mL) at room temperature. The resulting mixture wasstirred at 50° C. for 8 hrs and K₂CO₃ (30 mg, 0.2 mmol) was added thereaction mixture. The resulting mixture was heated at 50° C. for 2 hrsbefore the reaction mixture was added by EtOAc (60 mL) and water (20mL). The mixture was extracted and organic layer was washed with brine(20 mL) and dried with MgSO₄. The organic layer was concentrated and theresidue was purified by ISCO to give4-Carbamoyl-4-{4-[4-(4-isopropyl-piperidine-1-sulfonyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a white solid (700 mg, 99% yield). ¹H NMR (DMSO-d₆)δ 0.78 (d, J=6.8 Hz, 6H, CH₃, CH₃), 0.88-1.04 (m, 1H, CH), 1.07-1.25 (m,2H, CH₂), 1.29-1.43 (m, 1H, CH), 1.57-1.73 (m, 2H, CH₂), 2.02-2.32 (m,6H, CH₂, CH₂, CH₂), 3.50 (s, 3H, CH₃), 3.69 (d, J=11.7 Hz, 2H, CH₂),4.46 (d, J=17.8 Hz, 1H, CHH), 4.59 (d, J=17.6 Hz, 1H, CHH), 4.75 (dd,J=4.7, 10.2 Hz, 1H, CHH), 5.38 (s, 2H, CH₂), 7.20 (s, 1H, NHH),7.26-7.35 (m, 2H, Ar), 7.42-7.52 (m, 1H, Ar), 7.60 (s, 1H, NHH),7.71-7.83 (m, 4H, Ar); LCMS MH=572.

Step 3:3-{4-[4-(4-Isopropyl-piperidine-1-sulfonyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred solution of methyl5-amino-4-(4-(4-(4-isopropylpiperidin-1-ylsulfonyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(700 mg, 1.2 mmol) in Tetrahydrofuran (12 mL) at 0° C. was addedPOTASSIUM TERT-BUTOXIDE (151 mg, 1.3 mmol) in one portion. The solutionwas stirred at 0° C. for 30 mins. The reaction mixture was diluted byEtOAc (80 mL) and added by HCl (1N, aq, 3 mL). The mixture was added byNaHCO₃ (sat. aq, 15 mL) and extracted. Organic layer was washed withbrine (30 mL) and dried by MgSO₄. The organic layer was concentrated andthe resulting white solid was purified by being stirred in EtOAc (10 mL)and Acetonitrile (10 mL) to give3-{4-[4-(4-Isopropyl-piperidine-1-sulfonyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (386 mg, 58% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 55/45, (CH₃CN/0.1% H₃PO₄), 5.76 min(96.6%); mp: 245-247° C.; ¹H NMR (DMSO-d₆) δ 0.78 (d, J=6.8 Hz, 6H, CH₃,CH₃), 0.97 (dd, J=5.5, 11.7 Hz, 1H, CH), 1.06-1.27 (m, 2H, CH₂), 1.36(dq, J=6.5, 13.1 Hz, 1H, CH), 1.57-1.71 (m, 2H, CH₂), 1.93-2.08 (m, 1H,CHH), 2.06-2.24 (m, 2H, CH₂), 2.36-2.48 (m, 1H, CHH), 2.54-2.65 (m, 1H,CHH), 2.83-3.01 (m, 1H, CHH), 3.62-3.78 (m, 2H, CH₂), 4.31 (d, J=17.4Hz, 1H, CHH), 4.47 (d, J=17.6 Hz, 1H, CHH), 5.13 (dd, J=5.1, 13.2 Hz,1H, CHH), 5.38 (s, 2H, CH₂), 7.25-7.42 (m, 2H, Ar), 7.43-7.58 (m, 1H,Ar), 7.68-7.86 (m, 4H, Ar), 10.99 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ19.28, 22.30, 27.75, 31.08, 31.39, 44.92, 46.29, 51.43, 68.45, 114.86,115.44, 127.56, 127.89, 129.80, 129.86, 133.30, 134.91, 141.89, 153.10,167.84, 170.92, 172.79; LCMS MH=540; Anal. Calcd for C₂₈H₃₃N₃O₆S+.3H₂O:C, 61.70; H, 6.21; N, 7.71; Found: C, 61.78; H, 6.00; N, 7.68.

5.1993-{1-OXO-4-[4-(4-PHENYL-PIPERAZINE-1-SULFONYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: 1-(4-Bromomethyl-benzenesulfonyl)-4-phenyl-piperazine

To the stirred solution of 1-phenylpiperazine (0.51 g, 3.14 mmol) andTRIETHYL AMINE (0.482 ml, 3.46 mmol) in diethyl ether (10 mL) at 0° C.was added solution of 4-(bromomethyl)benzene-1-sulfonyl chloride (0.847g, 3.14 mmol) in ether (5 mL) drop wise. The resulting suspension wasstirred at 0° C. for 1.5 hr. The reaction mixture was added byacetonitrile (30 mL) and EtOAC (100 mL) followed by the addition ofwater (30 mL). The mixture was filtered to give a white solid. Thefiltrate was extracted. Organic layer was dried by MgSO₄ andconcentrated under vacuo. The residue combined with the white solid waspurified by ISCO to give1-(4-Bromomethyl-benzenesulfonyl)-4-phenyl-piperazine as a white solid(760 mg, 61% yield). ¹H NMR (DMSO-d₆) δ 2.95-3.08 (m, 4H, CH₂, CH₂),3.13-3.25 (m, 4H, CH₂, CH₂), 4.80 (s, 2H, CH₂), 6.75-6.85 (m, 1H, Ar),6.90 (d, J=7.9 Hz, 2H, Ar), 7.10-7.29 (m, 2H, Ar), 7.57-7.90 (m, 4H,Ar); LCMS MH=395, 397.

Step 2:4-Carbamoyl-4-{1-oxo-4-[4-(4-phenyl-piperazine-1-sulfonyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester

Methyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (360mg, 1.2 mmol), 1-(4-(bromomethyl)phenylsulfonyl)-4-phenylpiperazine (584mg, 1.5 mmol) and POTASSIUM CARBONATE (204 mg, 1.5 mmol) were mixed inAcetonitrile (15 mL) at room temperature. The resulting mixture wasstirred at 50° C. for 20 hrs and K₂CO₃ (15 mg, 0.1 mmol) was added tothe reaction mixture. The resulting mixture was stirred at 50° C. for1.5 hrs before it was added by EtOAc (50 mL) and water (20 mL). Theresulting mixture was extracted and the organic layer was washed withbrine (20 mL). The organic layer was concentrated under vacuo and theresidue was purified by ISCO to give4-Carbamoyl-4-{1-oxo-4-[4-(4-phenyl-piperazine-1-sulfonyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a white solid (730 mg, 98% yield); ¹H NMR (DMSO-d₆)δ 2.01-2.33 (m, 4H, CH₂, CH₂), 2.96-3.09 (m, 4H, CH₂, CH₂), 3.14-3.26(m, 4H, CH₂, CH₂), 3.50 (s, 3H, CH₃), 4.46 (d, J=17.8 Hz, 1H, CHH), 4.59(d, J=17.8 Hz, 1H, CHH), 4.74 (dd, J=4.7, 10.2 Hz, 1H, CHH), 5.40 (s,2H, CH₂), 6.80 (t, J=7.3 Hz, 1H, Ar), 6.90 (d, J=7.9 Hz, 2H, Ar),7.15-7.24 (m, 3H, Ar, NH), 7.25-7.35 (m, 2H, Ar), 7.40-7.51 (m, 1H, Ar),7.59 (s, 1H, NHH), 7.74-7.89 (m, 4H, Ar); LCMS MH=607.

Step 3:3-{-Oxo-4-[4-(4-phenyl-piperazine-1-sulfonyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred solution of methyl5-amino-5-oxo-4-(1-oxo-4-(4-(4-phenylpiperazin-1-ylsulfonyl)benzyloxy)isoindolin-2-yl)pentanoate(730 mg, 1.2 mmol) in Tetrahydrofuran (15 mL) at 0° C. was addedpotassium tert-butoxide (127 mg, 1.3 mmol) in one portion. The mixturewas stirred at 0° C. for 10 mins before it was added by HCl (1N, aq, 3mL) at 0° C. followed by the addition of DCM (50 mL) and NaHCO₃ (sat.aq, 15 mL). White solid was precipitated out. The mixture was filteredand the filtrate was extracted. The organic layer was concentrated undervacuo. The residue combined with the solid was purified by being stirredin mixed solvent of THF (3 mL) and DCM (25 mL) followed by thetriturating in DMF (5 mL) at 80° C. to give3-{1-Oxo-4-[4-(4-phenyl-piperazine-1-sulfonyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (256 mg, 37% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 50/50, (CH₃CN/0.1% H₃PO₄), 5.15 min(98.9%); mp: 302-304° C.; ¹H NMR (DMSO-d₆) δ 1.93-2.06 (m, 1H, CHH),2.35-2.47 (m, 1H, CHH), 2.53-2.65 (m, 1H, CHH), 2.83-3.08 (m, 5H, CH₂,CH₂, CHH), 3.14-3.26 (m, 4H, CH₂, CH₂), 4.30 (d, J=17.6 Hz, 1H, CHH),4.47 (d, J=17.6 Hz, 1H, CHH), 5.12 (dd, J=5.0, 13.3 Hz, 1H, CHH), 5.40(s, 2H, CH₂), 6.80 (t, J=7.3 Hz, 1H, Ar), 6.90 (d, J=7.9 Hz, 2H, Ar),7.20 (dd, J=7.3, 8.6 Hz, 2H, Ar), 7.27-7.40 (m, 2H, Ar), 7.44-7.56 (m,1H, Ar), 7.72-7.85 (m, 4H, Ar), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.30, 31.08, 44.95, 45.70, 47.82, 51.46, 68.46, 114.87, 115.46, 116.04,119.58, 127.79, 127.98, 128.86, 129.79, 129.88, 133.32, 133.96, 142.34,150.22, 153.10, 167.83, 170.88, 172.74; LCMS MH=575; Anal. Calcd forC₃₀H₃₀N₄O₆S+.3H₂O: C, 62.12; H, 5.32; N, 9.66; Found: C, 62.05; H, 5.18;N, 9.63.

5.2002-(2,6-DIOXOPIPERIDIN-3-YL)-4-((4-(HYDROXYMETHYL)BENZYL)OXY)ISOINDOLINE-1,3-DIONE

3-Aminopiperidine-2,6-dione hydrochloride (0.915 g, 5.56 mmol) was addedto a solution of 3-(4-(hydroxymethyl)benzyloxy)phthalic acid (1.4 g,4.63 mmol) in dry pyridine (15 mL) and the mixture was heated to 118° C.in an oil bath for 16 h. The dark reaction mixture was allowed to coolto room temperature and was acidified with slow addition of 1 N HCl (˜25mL). The mixture was further diluted with water (˜170 mL) and thensonicated for ˜30 minutes to help break up solid aggregates. Theresulting dark slurry was filtered on a medium pore fritted funnel andthe dark solid was washed with additional water (70 mL). The cake wassuction dried and then placed in vacuum oven at 60° C. for 2.5 h to give1.6 g of a dark blue solid. The solid was dissolved in a mixture of DCM,MeCN, and MeOH (˜100 mL each) and treated decolorizing charcoal. Themixture was swirled around and then gravity-filtered using filter paper.The filtrate/wash (dark amber color) was treated once again withdecolorizing charcoal and then filtered on a bed of celite. The clearfiltrate was concentrated in vacuo to dryness to give a solid which wastriturated with water and filtered with suction. The cake was washedwith additional water (˜100 mL), suction dried, and then placed invacuum oven at 60° C. for 4 h to give2-(2,6-dioxopiperidin-3-yl)-4-((4-(hydroxymethyl)benzyl)oxy)isoindoline-1,3-dioneas an off-white solid (1.2 μm, 68% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 5.08 min(99.9%); mp: 250-252; ¹H NMR (DMSO-d₆) δ 1.95-2.07 (m, 1H, CHH),2.41-2.67 (m, 2H, CHH, CHH), 2.78-3.00 (m, 1H, CHH), 4.50 (d, J=5.1 Hz,2H, CH₂OH), 5.09 (dd, J=5.4, 12.7 Hz, 1H, CH), 5.19 (t, J=5.6 Hz, 1H,OH), 5.36 (s, 2H, CH₂O), 7.24-7.40 (m, 2H, Ar), 7.41-7.53 (m, 3H, Ar),7.59 (d, J=8.5 Hz, 1H, Ar), 7.82 (dd, J=7.4, 8.5 Hz, 1H, Ar), 11.11 (s,1H, NH); ¹³C NMR (DMSO-d₆) δ 21.88, 30.83, 48.67, 62.53, 69.91, 115.40,116.52, 120.18, 126.44, 127.09, 133.17, 134.31, 136.86, 142.32, 155.42,165.21, 166.68, 169.81, 172.66. LCMS: M+Na=417; MH is not observed inpositive ionization mode; Anal Calcd for C₂₁H₁₈N₂O₆: C, 63.96; H, 4.60;N, 7.10; Found: C, 63.77; H, 4.52; N, 7.32.

5.2013-(4-((4-(4-METHYLPIPERAZINE-1-CARBONYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONEHYDROCHLORIDE

To a stirred suspension of3-(1-oxo-4-(4-(piperazine-1-carbonyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dionehydrochloride (100 mg, 0.200 mmol) in DMF (2 mL), was added 1 N aqsodium bicarbonate (0.441 mL, 0.441 mmol) followed by iodomethane (0.014mL, 0.220 mmol). The mixture was stirred at room temperature. Afterabout 24 h, an additional 5 μl of iodomethane was charged and themixture was stirred at room temperature for 3 days. The reaction mixturewas concentrated in vacuo and the residue was partitioned between EtOAc(100 mL) and 1N aq. NaHCO₃ (10 mL). The organic layer was washed withadditional water (40 mL) and brine, then dried over Na₂SO₄, andconcentrated in vacuo. The crude product was purified by prep HPLC andthe product was eluted with an acetonitrile/water gradient (0.1% formicacid in both mobile phases, 5% to 30% MeCN over 20 minutes) andfractions were collected by mass trigger. The desired fractions werecombined and treated with 1 N HCl (4 mL). The solution was concentratedto dryness and the residue was treated with 2 N HCl in Et₂O (0.5 mL).The volatiles were again concentrated dryness and the remaining solidwas dried in a vacuum oven to give3-(4-((4-(4-methylpiperazine-1-carbonyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride as an off-white solid (41 mg, 39%): HPLC: Waters SymmetryC₁₈, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 4.88min (95.7%): HPLC: Waters Symmetry C₁₈, 5 m, 3.9×150 mm, 1 ml/min, 240nm, 15/85 CH₃CN/0.1% H₃PO₄, 4.88 min (95.7%); mp: 360-362° C.; ¹H NMR(DMSO-d₆) δ 1.88-2.09 (m, 1H, CHH), 2.33-2.47 (m, 1H, CHH), 2.53-2.67(m, 1H, CHH), 2.67-2.83 (m, 3H, CH₃), 2.83-3.00 (m, 1H, CHH), 3.02-3.22(m, 2H, CH₂), 3.23-3.64 (m, 4H, CH₂, CH₂), 4.28 (d, J=17.6 Hz, 1H, CHH),4.45 (d, J=17.6 Hz, ¹H, CHH), 4.98-5.21 (m, 0.1H, CH), 5.32 (s, 2H,CH₂), 7.22-7.42 (m, 2H, Ar), 7.46-7.55 (m, 3H, Ar), 7.56-7.63 (m, 2H,Ar), 10.98 (s, 1H, NH), 11.31-11.77 (m, 1H, HCl); ¹³C NMR (DMSO-d₆) δ24.21, 33.00, 43.95, 47.07, 53.53, 53.79, 70.87, 73.78, 116.96, 117.34,129.26, 129.44, 131.81, 135.14, 136.04, 140.55, 155.19, 170.00, 170.91,172.79, 174.75; LCMS: MH=477; Anal Calcd for C₂₆H₂₈N₄O₅.HCl: C, 60.88;H, 5.70; N, 10.92; Found: C, 37.90; H, 4.33; N, 6.65.

5.2023-{4-[4-(4-ACETYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To a stirred solution of4-carbamoyl-4-[4-(4-chloromethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (600 mg, 1.392 mmol) in acetonitrile (10 mL), wasadded 1-(piperazin-1-yl)ethanone (178 mg, 1.392 mmol) and DIPEA (0.608ml, 3.48 mmol). The reaction was stirred at room temperature for 20hours, at 40° C. for 2.5 hours and at 50° C. for 3 hours before thereaction stopped proceeding. The reaction mixture was diluted bydichloromethane (40 mL) and washed with water (15 mL) and brine (15 mL).The organic layer was dried by MgSO₄ and concentrated to give4-{4-[4-(4-Acetyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester as a clear oil (840 mg, 115% crude yield). Thecompound was put to next step without further purification; LCMS MH=523.

Step 2: KOtBu (156 mg, 1.393 mmol) was added to the stirred solution ofmethyl4-(4-(4-((4-acetylpiperazin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(728 mg, 1.393 mmol) in tetrahydrofuran (10 mL) at 0° C. The reactionmixture was stirred at 0° C. for 1 hour before KOtBu (30 mg, 0.27 mmol)was added. The resulting mixture was stirred at room temperature for 10minutes and the reaction was complete. The reaction mixture was dilutedby dichloromethane (50 mL) and acidified with HCl (1N aq. 4 mL). Themixture was extracted with NaHCO₃ (10 mL) and brine (10 mL). The aqueouslayer was back extracted with dichloromethane (2×15 mL). Organic layerswere combined and dried by MgSO₄. The mixture was filtered andconcentrated to give a white solid. The solid was triturated in diethylether (30 mL) and filtered to give3-{4-[4-(4-acetyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (500 mg, 67.5% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 15/85, (acetonitrile/0.1% H₃PO₄),4.03 min (99.4%); mp: 208-210° C.; ¹H NMR (DMSO-d₆) δ 1.90-2.05 (m, 4H,CH₃, CHH), 2.23-2.40 (m, 4H, CH₂, CH₂), 2.40-2.48 (m, 1H, CHH),2.53-2.64 (m, 1H, CHH), 2.80-3.00 (m, 1H, CHH), 3.36-3.46 (m, 4H, CH₂,CH₂), 3.49 (s, 2H, CH₂), 4.26 (d, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.4Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.23 (s, 2H, CH₂),7.33 (d, J=7.6 Hz, 4H, Ar), 7.37-7.61 (m, 3H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 21.12, 22.33, 31.18, 40.77, 45.06, 45.60, 51.55,52.19, 52.74, 61.49, 69.36, 114.96, 115.22, 127.64, 128.94, 129.80,129.93, 133.28, 135.33, 137.70, 153.48, 167.97, 168.03, 170.96, 172.81;LCMS MH=491; Anal. Calcd for C₂₇H₃₀N₄O₅+0.3H₂O: C, 65.39; H, 6.22; N,11.30; Found: C, 65.31; H, 6.34; N, 11.32.

5.2033-{4-[4-(4-CYCLOPROPANECARBONYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To a stirred solution of methyl5-amino-4-(4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(600 mg, 1.392 mmol) in acetonitrile (10 mL) at room temperature, wasadded cyclopropyl(piperazin-1-yl)methanone (0.257 ml, 1.810 mmol) andDIPEA (0.608 ml, 3.48 mmol). The resulting light green solution wasstirred at room temperature for 3 days and the reaction was complete.The reaction mixture was diluted by dichloromethane (40 mL) andextracted with water (15 mL) and brine (15 mL). The organic layer wasdried by MgSO₄. The mixture was concentrated to give4-carbamoyl-4-{4-[4-(4-cyclopropanecarbonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a clear oil (900 mg, 118% crude yield). Thecompound was put to next step without further purification: LCMS MH=549.

Step 2: KOtBu (203 mg, 1.810 mmol) was added to a stirred solution ofmethyl5-4-carbamoyl-4-{4-[4-(4-cyclopropanecarbonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester (764 mg, 1.392 mmol) in tetrahydrofuran (10 mL) at 0°C. The resulting yellow solution was stirred at 0° C. for 30 minutes andthe reaction was complete. The reaction was diluted by dichloromethane(60 mL) and quenched at 0° C. with HCl (1N, aq, 3 mL) to pH=2. Themixture was added by NaHCO₃ (aq. sat., 10 mL) and brine (15 mL). Themixture was extracted and the aqueous layer was back extracted withdichloromethane (2×25 mL). The organic layers were combined and dried byMgSO₄. The mixture was filtered and concentrated. The residue wastriturated in diethyl ether (50 mL) and filtered to give3-{4-[4-(4-cyclopropanecarbonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (578 mg, 80% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 15/85, (acetonitrile/0.1% H₃PO₄),7.29 min (99.8%); mp: 233-235° C.; ¹H NMR (DMSO-d₆) δ 0.60-0.77 (m, 4H,CH₂, CH₂), 1.87-2.08 (m, 2H, CH₂), 2.24-2.48 (m, 5H, CHH, CH₂, CH₂),2.54-2.63 (m, 1H, CHH), 2.82-3.00 (m, 1H, CHH), 3.39-3.55 (m, 4H, CH₂,CH₂), 3.57-3.74 (m, 2H, CH₂), 4.26 (d, J=17.4 Hz, 1H, CHH), 4.42 (d,J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.23 (s, 2H,CH₂), 7.28-7.39 (m, 4H, Ar), 7.41-7.54 (m, 3H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 6.83, 10.05, 22.27, 31.11, 41.46, 44.70, 44.99,51.48, 52.20, 52.87, 61.44, 69.30, 114.89, 115.15, 127.57, 128.89,129.73, 129.86, 133.23, 135.26, 137.65, 153.41, 167.92, 170.78, 170.89,172.74; LCMS MH=517; Anal. Calcd for C₂₉H₃₂N₄O₅+0.2H₂O: C, 66.96; H,6.28; N, 10.77; Found: C, 66.90; H, 6.41; N, 10.71.

5.2043-{4-[4-(4-FLUORO-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To the stirred solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(600 mg, 1.392 mmol) and 4-fluoropiperidine hydrochloride (233 mg, 1.671mmol) in acetonitrile (10 mL) under a N₂ atmosphere, was added by DIPEA(0.608 ml, 3.48 mmol). The resulting solution was stirred at roomtemperature for 2 hours and at 70° C. for 3 hours before K₂CO₃ (192 mg,1.392 mmol) was added to the reaction mixture. The resulting mixture washeated at 50° C. overnight. K₂CO₃ (40 mg, 0.29 mmol) and4-fluoropiperidine hydrochloride (35 mg, 0.25 mmol) were added to thereaction mixture, which was stirred at 60° C. for 7 hours. The reactionmixture was diluted by dichloromethane (50 mL) and extracted with brine(20 mL). Organic layer was dried by MgSO₄ and concentrated down to give4-carbamoyl-4-{4-[4-(4-fluoro-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a light green stick oil (760 mg, 110% crude yield).The compound was put to next step as is: LCMS MH=498.

Step 2: KOtBu (203 mg, 1.810 mmol) was added to the stirred solution of4-carbamoyl-4-{4-[4-(4-fluoro-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester (693 mg, 1.392 mmol) in tetrahydrofuran (10 mL) at 0°C. under a N₂ atmosphere. The reaction mixture was stirred at 0° C. for30 minutes and the reaction was complete. The reaction mixture wasdiluted by dichloromethane (50 mL) and added by HCl (1N, aq, 4 mL) toPH=1. The mixture was extracted with a mixture of NaHCO₃ (aq, sat., 10mL) and brine (15 mL). The aqueous layer was back extracted withdichloromethane (2×25 mL). Organic layers were combined and dried MgSO₄.The mixture was filtered and concentrated. The residue was purified byISCO chromatography to give3-{4-[4-(4-fluoro-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (215 mg, 33% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 18/82, acetonitrile/0.1% H₃PO₄),4.02 min (98.9%); mp: 141-143° C.; ¹H NMR (DMSO-d₆) δ 1.57-2.06 (m, 5H,CHH, CH₂, CH₂), 2.19-2.34 (m, 2H, CH₂), 2.35-2.55 (m, 3H, CH₂, CHH),2.54-2.63 (m, 1H, CHH), 2.82-3.01 (m, 1H, CHH), 3.47 (s, 2H, CH₂), 4.25(d, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 4.52-4.82 (m, 1H,CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.22 (s, 2H, CH₂), 7.26-7.37(m, 4H, Ar), 7.40-7.56 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆)δ 22.29, 31.09 (d, J=19.8 Hz, M₁₉), 31.10, 45.00, 48.92 (d, J_(C-F)=6.6Hz), 51.49, 61.43, 69.34, 88.43 (d, J=168.4 Hz, M₁₄), 114.87, 115.15,127.56, 28.74, 129.73, 129.87, 133.23, 135.12, 138.21, 153.44, 167.93,170.90, 172.76; LCMS MH=466; Anal. Calcd for C₂₆H₂₈FN₃O₄+0.2H₂O: C,66.57; H, 6.10; N, 8.96; Found: C, 66.35; H, 6.29; N, 8.79.

5.2053-{4-[4-(4,4-DIFLUORO-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To the stirred solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(500 mg, 1.160 mmol) and 4,4-difluoropiperidine hydrochloride (274 mg,1.741 mmol) in acetonitrile (10 mL) under a N₂ atmosphere, were addedNa₂CO₃ (160 mg, 1.160 mmol) and DIPEA (0.507 ml, 2.90 mmol). Theresulting solution was stirred at 50° C. for 8 hours and the reactionwas stopped. The reaction mixture was diluted by dichloromethane (50 mL)and extracted with brine (20 mL). The organic layer was dried by MgSO₄and concentrated under vacuo to give4-carbamoyl-4-{4-[4-(4,4-difluoro-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as an off white solid (630 mg, 105% crude yield). Theproduct was put to next step as it was: LCMS MH=516.

Step 2: To the stirred solution of4-carbamoyl-4-{4-[4-(4,4-difluoro-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester (630 mg, 1.222 mmol) in THF (10 mL) at 0° C., wasadded by KOtBu (151 mg, 1.344 mmol). The mixture was stirred at 0° C.for 5 minutes and the reaction was complete. The reaction mixture wasdiluted by dichloromethane (50 mL) and acidified by HCl (1N, aq. 3 mL)to pH=2. The mixture was extracted with the mixture of NaHCO₃ (aq. sat.,5 mL) and brine (10 mL). The organic layer was dried by MgSO₄ andconcentrated. The residue was stirred in ether (50 mL) and the mixturefiltered to give the white solid. The solid was triturated in EtOAc (5mL) and filtered to give3-{4-[4-(4,4-difluoro-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (215 mg, 36%): HPLC: Waters Symmetry C-18, 3.9×150 mm,5 μm, 1 mL/min, 240 nm, 18/82 (acetonitrile/0.1% H₃PO₄): t_(R)=4.17(99.4%); mp: 193-195° C.; ¹H NMR (DMSO-d₆) δ 1.84-2.09 (m, 5H, CH₂, CH₂,CHH), 2.34-2.49 (m, 5H, CHH, CH₂, CH₂), 2.54-2.64 (m, 1H, CHH),2.81-3.02 (m, 1H, CHH), 3.55 (s, 2H, CH₂), 4.25 (d, J=17.6 Hz, 1H, CHH),4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.23(s, 2H, CH₂), 7.33 (d, 4H, M₀₁), 7.40-7.54 (m, 3H, Ar), 10.97 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 22.29, 31.12, 33.25 (t, J_(C-F)=20.9 Hz),45.00, 49.12, 51.51, 60.40, 69.29, 114.89, 115.16, 122.68 (t,J_(C-F)=239.9 Hz), 127.60, 128.84, 129.73, 129.88, 133.24, 135.32,137.72, 153.42, 167.93, 170.91, 172.76; LCMS MH=484; Anal. Calcd forC₂₆H₂₇F₂N₃O₅+1 H₂O: C, 62.27; H, 5.83; N, 8.39; Found: C, 62.09; H,5.73; N, 8.17.

5.206N-(1-{4-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-BENZYL}-PIPERIDIN-4-YL)-ACETAMIDE

Step 1: To the stirred solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (500 mg, 1.160 mmol) in acetonitrile (10mL), were added N-(piperidin-4-yl)acetamide (215 mg, 1.509 mmol),N-ethyl-N-isopropyl propan-2-amine (0.405 ml, 2.321 mmol) and K₂CO₃ (160mg, 1.160 mmol). The resulting reaction mixture was stirred at 50° C.for 2 hours and at room temperature overnight. The reaction mixture wasdiluted by dichloromethane (70 mL) and extracted with brine (20 mL). Theorganic layer was dried by MgSO₄ and concentrated to give4-{4-[4-(4-acetylamino-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester as a sticky oil (705 mg, 113% crude yield). Thecompound was used as it was: LCMS MH=537.

Step 2: KOtBu (130 mg, 1.160 mmol) was added to the suspension of4-{4-[4-(4-acetylamino-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester (622 mg, 1.16 mmol) in tetrahydrofuran (10 mL) at 0°C. The resulting yellow mixture was stirred at room temperature for 7hours and KOtBu (60 mg, 0.46 mmol) was added to the reaction mixture atroom temperature. The reaction was complete in 10 minutes. The reactionmixture was diluted by dichloromethane (30 mL) and acidified by HCl (1N,aq. 4 mL) and then neutralized by NaHCO₃ (sat., aq. 5 mL). The mixturewas extracted with brine (10 mL). The organic layer was dried by MgSO₄and concentrated to give white solid which was triturated by ether (30mL). The mixture was filtered to giveN-(1-{4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-11H-isoindol-4-yloxymethyl]-benzyl}-piperidin-4-yl)-acetamide as a whitesolid (293 mg, 50% yield): HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm,1 mL/min, 240 nm, 15/85, (acetonitrile/0.1% H₃PO₄), 4.85 min (99.1%);mp: 270-272° C.; ¹H NMR (DMSO-d₆) δ 1.26-1.44 (m, 2H, CH₂), 1.62-1.73(m, 2H, CH₂), 1.77 (s, 3H, CH₃), 1.89-2.05 (m, 3H, CHH, CH₂), 2.34-2.47(m, 1H, CHH), 2.54-2.64 (m, 1H, CHH), 2.65-2.79 (m, 2H, CH₂), 2.81-2.99(m, 1H, CHH), 3.40-3.57 (m, 3H, CH₂, CHH), 4.25 (d, J=17.6 Hz, 1H, CHH),4.42 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.22(s, 2H, CH₂), 7.24-7.38 (m, 4H, Ar), 7.38-7.56 (m, 3H, Ar), 7.74 (d,J=7.7 Hz, 1H, NH), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 22.69,31.18, 31.60, 45.07, 45.86, 51.55, 51.94, 61.80, 69.41, 114.94, 115.20,127.61, 128.78, 129.80, 129.93, 133.28, 135.12, 138.50, 153.49, 167.99,168.23, 170.96, 172.81; LCMS MH=505; Anal. Calcd for C₂₈H₃₂N₄O₅+0.5H₂O:C, 65.48; H, 6.48; N, 10.91; Found: C, 65.58; H, 6.40; N, 10.76.

5.2073-(4-(4-((2,6-DIMETHYLPIPERIDIN-1-YL)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: To the CNCH₃ solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 1.052 mmol), was added Cis-2,6-dimethylpiperidine (0.354 ml,2.63 mmol). The mixture was stirred at 50° C. overnight. The reactionmixture was filtered. The filtrate was concentrated on rota-vap to givemethyl5-amino-4-(4-(4-((2,6-dimethylpiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas a solid (0.6 g, 112%). It was used in the next step without furtherpurification.

Step 2: To the THF solution of methyl5-amino-4-(4-(4-((2,6-dimethylpiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.6 g, 1.182 mmol) at 0° C., was added potassium tert-butoxide (0.133g, 1.182 mmol). The mixture was stirred at 0° C. for 10 minutes. Themixture was quenched with 1N HCl solution (2 mL) followed by 20 mL ofNaHCO₃ (saturated) and EtOAc (20 mL). After extraction, organic layerwas washed with 20 mL of water, then brine (10 mL), and concentrated togive3-(4-(4-((2,6-dimethylpiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas white solid (0.33 g, 59%). mp: 205-207° C. HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1%H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R)=4.74 min (96%). ¹H NMR (DMSO-d₆) δ 0.94 (d, J=6.2 Hz, 6H, CH₃,CH₃), 1.14-1.38 (m, 3H, CHH, CH₂), 1.42-1.74 (m, 3H, CH₂, CHH),1.87-2.06 (m, 1H, CHH), 2.34-2.47 (m, 3H, CH₂, CHH), 2.53-2.65 (m, 1H,CHH), 2.81-3.02 (m, 1H, CHH), 3.70 (s, 2H, CH₂), 4.19-4.48 (m, 2H, CH₂),5.11 (dd, J=5.0, 13.1 Hz, 1H, NCH), 5.20 (s, 2H, CH₂), 7.33 (dd, J=2.6,7.7 Hz, 2H, Ar), 7.39 (s, 4H, Ar), 7.43-7.56 (m, 1H, Ar), 10.97 (s, 1H,NH). ¹³C NMR (DMSO-d₆) δ 21.98, 22.31, 23.66, 31.15, 34.04, 45.03,51.51, 53.56, 57.41, 69.50, 114.88, 115.13, 127.26, 127.41, 129.75,129.90, 133.24, 134.00, 142.84, 153.52, 167.96, 170.91, 172.76; LCMS:476; Anal Calcd for C₂₈H₃₃N₃O₄+0.4H₂O: C, 69.66; H, 7.06; N, 8.70;Found: C, 69.46; H, 7.10; N, 8.41.

5.2083-{1-OXO-4-[4-(4-PHENYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To a stirred solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.60 g, 1.39 mmol) in acetonitrile (15 ml) at room temperature, wasadded 4-phenylpiperidine (0.27 g, 1.67 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.28 ml, 1.67 mmol). The mixture wasstirred at 50° C. for a couple of hours and evaporated to give an oil(1.20 g, 86% crude yield).

Step 2: To a stirred solution of methyl5-amino-5-oxo-4-(1-oxo-4-(4-((4-phenylpiperidin-1-yl)methyl)benzyloxy)isoindolin-2-yl)pentanoate(0.77 g, 1.39 mmol) in THF (15 ml) in an ice bath, was added potassium2-methylpropan-2-olate (0.31 g, 2.79 mmol), and the mixture was stirredfor ten minutes. The mixture was quickly quenched by 1 N HCl (4 ml) andimmediately neutralized by saturated sodium bicarbonate (5.5 ml topH=7). The mixture was then stirred with ethyl acetate (25 ml). Organicphase was separated, washed with brine (15 ml), and concentrated to alight yellow solid, which was purified on silica gel column (MeOH/CH₂Cl₂gradient from 1% to 7% in 20 min) to give3-{1-Oxo-4-[4-(4-phenyl-piperidin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.42 g, 58% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄), 4.80 min(96.3%); mp: 220-222° C.; 1H NMR (DMSO-d₆) δ 0.08-0.10 (d, 2H, CH₂),1.64-1.72 (m, 4H, CH₂, CH₂), 1.96-2.07 (m, 3H, CH, CH₂), 2.39-2.42 (m,1H, CHH), 2.51-2.60 (m, 1H, CHH), 2.85-2.97 (3H, CHH, CH₂), 3.52 (br. s,2H, CH₂), 4.23-4.45 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH),5.24 (s, 2H, CH₂), 7.15-7.52 (m, 12H, Ar), 10.97 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.34, 31.18, 32.94, 41.69, 45.07, 51.55, 53.52, 62.05,69.40, 114.96, 115.22, 125.97, 126.64, 127.64, 128.29, 129.00, 129.81,129.94, 133.30, 135.21, 138.37, 146.19, 153.50, 167.99, 170.97, 172.82;LCMS MH=524; Anal. Calcd for C₃₂H₃₃N₃O₄: (+0.50H₂O): C, 72.16; H, 6.43;N, 7.89; Found: C, 71.83; H, 6.31; N, 7.80.

5.2093-{4-[4-(4-CYCLOPROPYLMETHYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To a solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.50 g, 1.06 mmol) in acetonitrile (50 mL), was added1-(cyclopropylmethyl)piperazine (0.35 ml, 2.33 mmol). The mixture wasstirred for one and a half hours and then concentrated to give4-carbamoyl-4-{4-[4-(4-cyclopropylmethyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a white foamy solid (0.83 g, 146% crude yield). Itwas used in the next step without further purification.

Step 2: To a stirred solution of methyl5-amino-4-(4-(4-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.57 g, 1.06 mmol) in THF (15 ml) in an ice bath was added potassium2-methylpropan-2-olate (0.29 g, 2.57 mmol). The mixture was stirred for15 minutes and was quenched with 1 N HCl (˜3 ml) and neutralized bysaturated sodium bicarbonate (6 ml to pH=7). The mixture was stirredwith ethyl acetate (20 ml), and then the organic phase was washed withbrine (15 ml), separated and concentrated to an off-white foamy solid.It was purified silica gel column (MeOH/CH₂Cl₂ gradient from 1% to 9% in70 min) to give3-{4-[4-(4-cyclopropylmethyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white powder (270 mg, 51% yield); mp: 176-178° C.; HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄),4.05 min (97.0%); ¹H NMR (DMSO-d₆) δ 0.08-0.10 (d, 2H, CH₂), 0.45-0.47(d, 2H, CH₂), 0.80-0.83 (m, 1H, CHH), 1.96-2.00 (m, 1H, CHH), 2.27-2.60(overlapped multiple peaks, 12H, CH₂, CH₂, CH₂, CH₂, CH₂, CHH, CHH),2.85-2.97 (m, 1H, CHH), 3.48 (s, 2H, CH₂), 4.22-4.44 (m, 2H, CH₂), 5.11(dd, J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.30-7.34 (m, 4H, Ar),7.45-7.51 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 3.69,7.75, 22.34, 31.18, 45.07, 51.55, 52.03, 52.37, 61.54, 62.36, 69.40,114.96, 115.22, 127.63, 128.89, 129.80, 129.93, 133.29, 135.24, 137.92,153.49, 167.99, 170.96, 172.82; LCMS MH=503; Anal. Calcd for C₂₉H₃₄N₄O₄:(+1.0H₂O): C, 66.90; H, 6.97; N, 10.76; Found: C, 66.67; H, 6.63; N,10.42.

5.2103-{4-[4-(4,4-DIMETHYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To a stirred solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.55 g, 1.28 mmol) in acetonitrile (15 ml) at room temperature, wereadded 4,4-dimethylpiperidine hydrochloride (0.23 g, 1.53 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.46 ml, 2.81 mmol). The mixture wasstirred overnight and then concentrated to give an oil, which waspurified on silica gel column (MeOH/CH₂Cl₂ gradient from 1% to 9% in 60min) to give4-carbamoyl-4-{4-[4-(4,4-dimethyl-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a light yellow solid (0.60 g, 92% yield). It wasused in the next step without further purification.

Step 2: To a stirred solution of methyl5-amino-4-(4-(4-((4,4-dimethylpiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.59 g, 1.16 mmol) in THF (15 ml) in an ice bath, was added potassium2-methylpropan-2-olate (0.33 g, 2.94 mmol). The mixture was stirred forten minutes and was quickly quenched by 1 N HCl (4 ml) and immediatelyneutralized by saturated sodium bicarbonate (5.5 ml to pH=7). Themixture was then stirred with ethyl acetate (25 ml). The organic phasewas separated, washed with brine (15 ml), and concentrated to anoff-white solid, which was purified on silica gel column (MeOH/CH₂Cl₂gradient from 1% to 9% in 40 min) to give3-{4-[4-(4,4-dimethyl-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a fine white powder (150 mg, 27% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄), 4.64 min(96.2%); mp: 168-170° C.; ¹H NMR (DMSO-d₆) δ 0.95 (s, 6H, 2CH₃), 1.49(br. s, 4H, CH₂, CH₂), 1.96-2.00 (m, 1H, CHH), 2.37-2.43 (m, 1H, CHH),2.51-2.60 (m, 1H, CHH), 2.86-2.98 (3H, CHH, CH₂), 3.50 (br. s, 2H, CH₂),4.23-4.45 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.25 (s, 2H,CH₂), 7.31-7.51 (m, 7H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.35, 27.94, 31.18, 37.16, 45.06, 48.91, 51.56, 69.28, 114.97, 115.26,127.69, 129.80, 129.94, 133.31, 153.44, 167.98, 170.97, 172.82; LCMSMH=476; Anal. Calcd for C₂₈H₃₃N₃O₄: C, 70.71; H, 6.99; N, 8.84; Found:C, 66.15; H, 6.50; N, 8.02.

5.2113-(4-(4-((4-ETHYLPIPERIDIN-1-YL)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: To the acetonitrile solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.64 g, 1.346 mmol), was added 4-ethylpiperidine (0.34 g, 3.00 mmol).The mixture was stirred at room temperature overnight and concentratedon rota-vap. The resulting solid was extracted with CH₂Cl₂ (25 mL) andwater (25 mL). The organic layer was washed with water (10 mL) thenbrine (10 mL), dried over Na₂SO₄, and concentrated to give methyl5-amino-4-(4-(4-((4-ethylpiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas an off-white foamy solid (0.67 g, 98%). The solid was used in thenext step without further purification.

Step 2: To the THF solution of methyl5-amino-4-(4-(4-((4-ethylpiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.67 g, 1.320 mmol) was added potassium 2-methylpropan-2-olate (0.148g, 1.320 mmol) at 0° C. The reaction was quenched by adding sat. NaHCO₃(5 mL) after stirring at 0° C. for 1.5 hours. The mixture was dilutedwith EtOAc (20 mL) and 10 mL of water, extracted, washed with brine. Theorganic layer was concentrated on rota-vap to give a yellow solid. Thesolid was partially dissolved in CH₂Cl₂ (10 mL), and ether (5 mL) wasadded. The mixture was stirred and filtered to give3-(4-(4-((4-ethylpiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a solid (250 mg, 40%). mp: 180-182° C. HPLC: Waters Symmetry C-18,3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1% H₃PO₄in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R)=4.85 min (96%). ¹H NMR (DMSO-d₆) δ 0.66-0.94 (m, 3H, CH₃),0.99-1.14 (m, 3H, CH, CH₂), 1.15-1.29 (m, 2H, CH₂), 1.47-1.71 (m, 2H,CH₂), 1.78-1.92 (m, 2H, CH₂), 1.93-2.06 (m, 1H, CH), 2.36-2.48 (m, 1H,CHH), 2.53-2.65 (m1H, CHH), 2.77 (d, J=10.8 Hz, 2H, CH₂), 2.83-3.03 (m,1H, CHH), 3.43 (s, 2H, CH₂), 4.13-4.50 (m, 2H, CH₂), 5.11 (dd, J=4.9,13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.21-7.38 (m, 4H, Ar), 7.39-7.55(m, 3H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 11.18, 22.36, 28.76,31.21, 31.65, 36.97, 45.09, 51.58, 53.37, 62.19, 69.47, 114.97, 115.21,127.61, 128.79, 129.81, 129.95, 133.31, 135.06, 138.66, 153.53, 168.01,170.96, 172.82; LCMS: 476; Anal Calcd for C₂₈H₃₈N₃O₄+0.8H₂O: C, 68.63;H, 7.12; N, 8.58; Found: C, 68.66; H, 6.83; N, 8.44.

5.2123-(4-(4-((4-ISOPROPYLPIPERIDIN-1-YL)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: To the acetonitrile solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 1.052 mmol), was added 4-isopropylpiperidine (0.294 g, 2.314mmol). The mixture was stirred at room temperature overnight. Thereaction mixture was concentrated on rota-vap. The resulting oil wastaken up in EtOAc (15 mL) and extracted with water (20 mL). The organiclayer was washed with brine (10 mL), dried over Na₂SO₄ and concentratedto give methyl5-amino-4-(4-(4-((4-isopropylpiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas an oil. The mixture was used without further purification in the nextstep.

Step 2: To the THF solution of methyl5-amino-4-(4-(4-((4-isopropylpiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.548 g, 1.05 mmol), was added potassium 2-methylpropan-2-olate (0.12g, 1.069 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes.The reaction was quenched by adding 2 mL of HCl (1N) and 5 mL of NaHCO₃(saturated) followed by 20 mL of EtOAc and 10 mL of water. The mixturewas extracted and the organic layer was washed with water (10 mL) andbrine (10 mL), and concentrated. The resulting solid was purified onISCO column to give3-(4-(4-((4-isopropylpiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas white solid (65 mg, 13%). mp: 124-126° C. HPLC: Waters Symmetry C-18,3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1% H₃PO₄in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R)=4.98 min (96.2%). ¹H NMR (DMSO-d₆) δ 0.83 (d, J=6.8 Hz, 6H, CH₃,CH₃), 0.90-1.06 (m, 1H, CH), 1.07-1.25 (m, 2H, CH₂), 1.31-1.47 (m, 1H,CH), 1.51-1.63 (m, 2H, CH₂), 1.76-1.92 (m, 2H, CH₂), 1.93-2.04 (m, 1H,CHH), 2.36-2.47 (m, 1H, CHH), 2.53-2.63 (m, 1H, CHH), 2.74-2.88 (m, 2H,CH₂), 2.88-3.00 (m, 1H, CHH), 3.40-3.46 (br. s., 2H, CH₂), 4.19-4.47 (m,2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂),7.25-7.37 (m, 4H, Ar), 7.38-7.54 (m, 3H, Ar), 10.97 (s, 1H, NH). 13C NMR(DMSO-d₆) δ 19.66, 22.36, 28.88, 31.21, 31.94, 41.84, 45.09, 51.58,53.63, 62.13, 69.45, 114.97, 115.21, 127.61, 128.80, 129.81, 129.95,133.31, 135.04, 153.51, 168.01, 170.96, 172.82; LCMS: 490; Anal Calcdfor C₂₉H₃₅N₃O₄+0.4H₂O: C, 70.11; H, 7.26; N, 8.46; Found: C, 70.10; H,7.37; N, 8.36.

5.2133-{4-[4-(4-METHOXY-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To the acetonitrile solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 1.052 mmol), were added 4-methoxypiperidine (0.133 g, 1.157mmol) and DIPEA (0.276 ml, 1.578 mmol). After stirred at roomtemperature overnight, the reaction mixture was concentrated onrota-vap, giving4-carbamoyl-4-{4-[4-(4-methoxy-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as an oil. It was used in the next step withoutfurther purification.

Step 2: To the THF solution of methyl5-amino-4-(4-(4-((4-methoxypiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.536 g, 1.052 mmol), was added potassium 2-methylpropan-2-olate (0.236g, 2.104 mmol) at 0° C. The mixture was stirred at this temperature for15 minutes. The reaction was quenched by adding 10 mL of 1N HCl followedby 25 mL of NaHCO₃ (sat). The mixture was extracted with EtOAc (30 mL).The organic layer was concentrated to give a yellowish solid. The solidwas stirred with ether overnight. The resulting suspension was filteredto give3-{4-[4-(4-methoxy-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas white solid (0.34 g, 71%). mp: 149-151° C. HPLC: Waters Symmetry C₁₈,5 μm, 3.9×150 mm, 1 mL/min, 240 nm, gradient to 95/5 acetonitrile/0.1%H₃PO₄ in 5 min: t_(R)=4.60 min (96%); ¹H NMR (DMSO-d₆) δ 1.28-1.51 (m,2H, CH₂), 1.70-1.87 (m, 2H, CH₂), 1.90-2.15 (m, 3H, CHH, CH₂), 2.34-2.45(m, 1H, CHH), 2.56-2.69 (m, 3H, CHH, CH₂), 2.80-3.01 (m, 1H, CHH),3.08-3.19 (m, 1H, CH), 3.21 (s, 3H, OCH₃), 3.44 (s, 2H, CH₂), 4.18-4.53(m, 2H, CH₂), 5.03-5.16 (m, 1H, NCH), 5.22 (s, 2H, CH₂), 7.23-7.38 (m,4H, Ar), 7.39-7.57 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.36, 30.63, 31.21, 50.48, 51.58, 54.77, 61.72, 69.44, 75.68, 114.95,115.21, 127.62, 128.79, 128.83, 129.81, 129.95, 133.31, 135.12, 138.51,153.51, 168.01, 170.96, 172.83; LCMS: 478; Anal Calcd forC₂₇H₃₁N₃O₅+0.1H₂O: C, 67.40; H, 6.58; N, 8.73; Found: C, 67.32; H, 6.39;N, 8.52.

5.2143-{4-4-(3,3-DIFLUORO-PIPERIDIN-1-YLMETHYL)-BENZYLOXY-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To the stirred solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(600 mg, 1.262 mmol) in acetonitrile (10 mL), were added3,3-difluoropiperidine hydrochloride (199 mg, 1.262 mmol) and DIPEA(0.441 ml, 2.52 mmol). The resulting solution was stirred at roomtemperature for two days. The mixture was concentrated and dissolved indichloromethane (30 mL) and back extracted with NaHCO₃ (aq, sat. 15 mL).The organic layer was concentrated to give4-carbamoyl-4-{4-[4-(3,3-difluoro-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as an off-white solid (651 mg, 100% crude yield). Thesolid was put to next step without further purification: LCMS MH=516.

Step 2: KOtBu (142 mg, 1.262 mmol) was added to a stirred solution of4-carbamoyl-4-{4-[4-(3,3-difluoro-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyric acid methyl ester (651 mg,1.262 mmol) in tetrahydrofuran (10 mL) at 0° C. The resulting reactionmixture was stirred at 0° C. for 30 minutes before it was diluted withdichloromethane (20 mL). The mixture was acidified with HCl (1N, 2 mL,aq.) and neutralized with NaHCO₃ (sat. aq. 2 mL) followed by theaddition of brine (8 mL) and dichloromethane (30 mL). The mixture wasextracted and the aqueous layer was back extracted with dichloromethane(2×40 mL). Organic layers were combined and dried with MgSO₄. Themixture was filtered and the filtrate was concentrated. The residue wastriturated in diethyl ether (50 mL) and filtered to give3-{4-[4-(3,3-difluoro-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (540 mg, 77% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 18/82, (acetonitrile/0.1% H₃PO₄),4.44 min (99.9%); mp: 140-142° C.; ¹H NMR (DMSO-d₆) δ 1.57-1.71 (m, 2H,CH₂), 1.76-2.08 (m, 3H, CH₂, CHH), 2.34-2.45 (m, 2H, CH₂), 2.45-2.47 (m,1H, CHH), 2.53-2.68 (m, 3H, CH₂, CHH), 2.81-3.01 (m, 1H, CHH), 3.57 (s,2H, CH₂), 4.20-4.32 (m, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.4 Hz, 1H,CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 7.28-7.38(m, 4H, Ar), 7.41-7.54 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆)δ 21.38-21.71, 22.33, 31.18, 31.61 (t, J_(C-F)=23.1 Hz), 45.07, 51.12,51.55, 57.48 (t, J_(C-F)=27.5 Hz), 60.56, 69.38, 114.94, 115.22, 121.05(t, J_(C-F)=241.0 Hz), 127.67, 128.82, 129.78, 129.93, 133.30, 135.40,137.34, 153.49, 167.99, 170.96, 172.81; LCMS MH=484; Anal. Calcd forC₂₆H₂₇F₂N₃O₄+1.3H₂O: C, 61.6; H, 5.89; N, 8.29; Found: C, 61.39; H,5.61; N, 8.00.

5.2153-(4-(4-((4-(METHYLSULFONYL)PIPERAZIN-1-YL)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a stirred solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.455 g, 1.056 mmol) in acetonitrile (10 ml), were added1-(methylsulfonyl)piperazine (0.225 g, 1.373 mmol) and DIPEA (0.436 ml,2.64 mmol). The reaction mixture was stirred at room temperature for 5.5days. The reaction mixture was diluted by dichloromethane (40 mL) andwashed with water (20 mL) and brine (20 mL). The organic layer was thendried (MgSO₄) and after filtration of drying agent, solvent wasconcentrated down to give methyl 5-amino-4-(4-(4-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate.The crude product was used in the next step without furtherpurification.

Potassium tert-butoxide (0.154 g, 1.373 mmol) was added to the stirredsolution of methyl5-amino-4-(4-(4-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.590 g, 1.056 mmol) in THF (20 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 1 hour. The reaction mixture was then diluted bydichloromethane (50 mL) and acidified with HCl (1N aq. 4 mL). Themixture was washed with NaHCO₃ (20 mL) and brine (20 mL). The aqueouslayer was extracted back with dichloromethane (2×30 mL). Combinedorganic layers were dried with MgSO₄. After filtration of drying agent,solvent was evaporated. The residue was stirred in a mixture ofmethanol/dichloromethane: 50/50. The filtrate was purified by Isco Flash(dry loading, gradient, Methanol/dichloromethane: 0/100 to 5/95 in 30min), eluting product at 5/95. The solvent was then evaporated and theresidue was stirred in ether. Solid was filtered and dried to give3-(4-(4-((4-(methylsulfonyl)piperazin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.32 g, 2 steps 58% yield); HPLC: Waters Symmetry C-18, 3.9×150 mm, 5μm, 1 mL/min, 240 nm, acetonitrile/0.1% H3PO4: gradient 10/90 to 90/10in 15 min; 5 min at 90/10: 6.23 min (97.27%), 8.02 min (2.25%); mp:158-160° C.; 1H NMR (DMSO-d6) δ 1.87-2.08 (m, 1H, CHH), 2.31-2.48 (m,5H, CH2, CH2, CHH), 2.53-2.69 (m, 1H, CHH), 2.86 (s, 3H, CH3), 2.89-3.02(m, 1H, CHH), 3.02-3.20 (m, 4H, CH2, CH2), 3.53 (s, 2H, CH2), 4.16-4.33(m, 1H, CHH), 4.34-4.53 (m, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH),5.23 (s, 2H, CH2), 7.25-7.40 (m, 4H, Ar), 7.40-7.55 (m, 3H, Ar), 10.97(s, 1H, NH); 13C NMR (DMSO-d6) δ 22.34, 31.18, 33.55, 45.06, 45.41,51.55, 51.71, 61.14, 69.35, 114.96, 115.22, 127.66, 128.90, 129.80,129.93, 133.28, 135.38, 137.69, 153.46, 167.97, 170.96, 172.81; AnalCalcd for C₂₆H₃₀N₄O₆S+0.2H2O: C, 58.90, H, 5.78, N, 10.57; Found: C,58.62, H, 5.51, N, 10.40.

5.2163-[1-OXO-4-(4-PIPERIDIN-1-YLMETHYL-BENZYLOXY)-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer-supported triphenylphosphene (1-1.5 mmol/g, 2.10 g, 2.63mmol) was added to a stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester in THF (20 mL) at 0° C., followed by addition ofdiisopropyl azodicarboxylate (0.52 mL, 2.63 mmol). After stirring for 15minutes, (4-piperidin-1-ylmethyl-phenyl)-methanol (0.49 g, 2.39 mmol)was added. The mixture was stirred at room temperature overnight andthen filtered. The filtrate was evaporated and purified on silica gelcolumn to give4-carbamoyl-4-[1-oxo-4-(4-piperidin-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as an oil (0.51 g, 88% yield).

Step 2: Potassium tert-butoxide (0.12 g, 1.06 mmol) was added to astirred solution of4-carbamoyl-4-[1-oxo-4-(4-piperidin-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.51 g, 1.06 mmol) in THF (8 mL) at 0° C. for 10minutes. The mixture was quenched with 1N HCl (2 ml) and neutralizedwith saturated sodium bicarbonate (4 ml to pH=8). The mixture was washedwith ethyl acetate (3×20 mL). The combined ethyl acetate phases wereevaporated and purified by PREP HPLC to give3-[1-oxo-4-(4-piperidin-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (0.07 g, 15% yield); HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 17/83 acetonitrile/0.1% H₃PO₄, 4.88 min(98.8%); mp: 186-188° C.; ¹H NMR (DMSO-d₆) d, 1.30-1.60 (m, 6H, 3CH₂),1.91-2.05 (m, 1H, CHH), 2.22-2.36 (m, 4H, 2CH₂), 2.37-2.47 (m, 1H, CHH),2.53-2.63 (m, 1H, CHH), 2.83-2.99 (m, 1H, CHH), 3.41 (s, 2H, CH₂),4.19-4.48 (m, 2H, ArCH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s,2H, CH₂), 7.26-7.37 (m, 4H, Ar), 7.39-7.53 (m, 3H, Ar), 10.97 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 22.36, 23.99, 25.55, 31.21, 45.10, 51.58,53.88, 62.54, 69.45, 114.97, 115.21, 127.59, 128.80, 129.81, 129.95,133.31, 135.03, 138.58, 153.51, 168.01, 170.96, 172.83; LCMS MH=448;Anal. Calcd for C₂₆H₂₉N₃O₄: C, 69.78; H, 6.53; N, 9.39. Found: C, 66.86;H, 6.15; N, 8.99.

5.2173-{4-[4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: Polymer-supported triphenylphosphene (1.6 mmol/g, 1.36 g, 1.85mmol) was added to a stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.45 g, 1.54 mmol) in THF (20 mL) at 0° C., followed byaddition of diisopropyl diazene-1,2-dicarboxylate (0.37 ml, 1.88 mmol).After stirring for 30 minutes,[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-methanol (0.41 g, 1.85 mmol)was added. The mixture was stirred for three hours then filtered, washedwith methanol (3×10 mL) and methylene chloride (3×10 mL). The combinedfiltrate was evaporated in vacuo to give an oil, which was purified onsilica gel column (amine column, MeOH/CH₂Cl₂ gradient from 0% to 2% in60 min) to give4-carbamoyl-4-{4-[4-(4-methyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a clear oil (0.50 g, 66% yield).

Step 2: Potassium tert-butoxide (0.11 g, 1.01 mmol) was added to astirred solution of4-carbamoyl-4-{4-[4-(4-methyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester (0.50 g, 1.01 mmol) in THF (15 mL) at 0° C. Themixture was stirred for ten minutes and quenched with 1N HCl (3 mL),neutralized by saturated sodium bicarbonate (4 mL to pH=7), and quicklyextracted by ethyl acetate (2×30 mL). The combined ethyl acetate phaseswere evaporated to give an off-white solid, which was stirred in ethylacetate (10 mL) for one hour. The suspension was filtered to give3-{4-[4-(4-methyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas an off-white solid (0.12 g, 26% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 10/90 in 15 min(acetonitrile/0.1% H₃PO₄), 9.82 min (99.7%); mp: 188-190° C.; ¹H NMR(DMSO-d₆) δ 1.90-2.04 (m, 1H, CHH), 2.14 (s, 3H, CH₃), 2.20-2.46 (m, 9H,CHH, CH₂CH₂, CH₂CH₂), 2.55-2.66 (m, 1H, CHH), 2.80-3.05 (m, 1H, CHH),3.45 (s, 2H, CH₂), 4.17-4.50 (m, 2H, CH₂), 5.11 (dd, J=5.2, 13.1 Hz, 1H,NCH), 5.22 (s, 2H, CH₂), 7.23-7.56 (m, 7H, Ar), 10.97 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 22.36, 31.21, 45.09, 45.72, 51.58, 52.52, 54.71, 61.74,69.44, 114.98, 115.23, 127.62, 128.88, 129.81, 129.95, 133.31, 135.17,138.18, 153.51, 168.01, 170.96, 172.82; LCMS MH=463; Anal. Calcd forC₂₆H₃₀N₄O₄: C, 67.51; H, 6.54; N, 12.11; Found: C, 67.23; H, 6.67; N,11.78.

5.2184-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester

Step 1: To the acetonitrile solution of4-carbamoyl-4-[4-(4-chloromethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.8 g, 1.8 mmol), was addedt-butyl-piperazine-carboxylate (0.86 g, 4.6 mmol) and DIPEA (0.62 mL,4.6 mmol). After stirred at room temperature overnight, the mixture wasconcentrated and extracted with EtOAc (30 mL) and Na₂CO₃ (20 mL). Theorganic layer was washed with water (20 mL) and brine (20 mL),concentrated to give4-{4-[2-(1-carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester as an oil, which was used in next step withoutpurification.

Step 2: To the THF solution (20 mL) of4-{4-[2-(1-carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester (1.04 g, 1.8 mmol), was added potassium t-butoxide(0.3 g, 2.7 mmol) at 0° C. The mixture was stirred for 15 minutes at 0°C. and quenched with 5 mL of 1N HCl solution followed by 15 mL ofsaturated NaHCO₃ solution. The mixture was extracted with EtOAc (20 mL).The organic layer was concentrated in vacuo. The resulting oil waspurified on silica gel column eluted with CH₂Cl₂ and methanol to give4-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester as a oil (170 mg, 18%). mp: 180-182° C. HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradientacetonitrile/0.1% H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at100/0 for 5 min: t_(R)=5.03 min (94%); LCMS MH=549. ¹H NMR (DMSO-d₆) δ1.38 (s, 9H, CH₃, CH₃, CH₃), 1.87-2.13 (m, 1H, CHH), 2.30 (t, J=4.8 Hz,4H, CH₂, CH₂), 2.40-2.48 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.81-3.00(m, 1H, CHH), 3.30 (br. s., 4H, CH₂, CH₂), 3.48 (s, 2H, CH₂), 4.14-4.57(m, 2H, CH₂), 5.00-5.17 (m, 1H, NCH), 5.23 (s, 2H, CH₂), 7.33 (d, J=7.7Hz, 4H, Ar), 7.45 (d, J=8.7 Hz, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.29, 27.96, 31.13, 45.02, 51.51, 52.28, 61.55, 69.33,78.64, 114.91, 115.18, 127.58, 128.90, 129.76, 129.89, 133.25, 135.25,137.70, 153.43, 153.71, 167.92, 170.91, 172.76; Anal Calcd forC₃₀H₃₆N₄O₆+0.2H₂O: C, 65.25; H, 6.64; N, 10.15; Found: C, 64.96; H,6.51; N, 10.11.

5.2193-[1-OXO-4-(4-PIPERAZIN-1-YLMETHYL-BENZYLOXY)-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the acetonitrile solution of 4-carbamoyl-4-[4-(4chlormethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyric acidmethyl ester (0.8 g, 1.8 mmol), were addedt-butyl-piperazine-carboxylate (0.86 g, 4.6 mmol) and DIPEA (0.62 mL,4.6 mmol). After being stirred at room temperature overnight, themixture was concentrated and extracted with EtOAc (30 mL) and Na₂CO₃ (20mL). The organic layer was washed with water (20 mL) and brine (20 mL),and concentrated to give4-{4-[2-(1-Carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester as an oil, which was used in next step withoutpurification.

Step 3: To the THF solution (20 mL) of4-{4-[2-(1-carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester (1.04 g, 1.8 mmol), was added potassium t-butoxide(0.3 g, 2.7 mmol) at 0° C. The mixture was stirred for 15 minutes at 0°C. and quenched with 5 mL of 1N HCl solution followed by 15 mL ofsaturated NaHCO₃ solution. The mixture was extracted with EtOAc (20 mL).The organic layer was concentrated in vacuo. The resulting oil waspurified on silica gel column eluted with CH₂Cl₂ and methanol to give4-{4-[2-(2,6-Dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester as a oil (170 mg, 18%). mp: 180-182° C. HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradientacetonitrile/0.1% H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at100/0 for 5 min: t_(R)=5.03 min (94%); LCMS MH=549. ¹H NMR (DMSO-d₆) δ1.38 (s, 9H, CH₃, CH₃, CH₃), 1.87-2.13 (m, 1H, CHH), 2.30 (t, J=4.8 Hz,4H, CH₂, CH₂), 2.40-2.48 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.81-3.00(m, 1H, CHH), 3.30 (br. s., 4H, CH₂, CH₂), 3.48 (s, 2H, CH₂), 4.14-4.57(m, 2H, CH₂), 5.00-5.17 (m, 1H, NCH), 5.23 (s, 2H, CH₂), 7.33 (d, J=7.7Hz, 4H, Ar), 7.45 (d, J=8.7 Hz, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.29, 27.96, 31.13, 45.02, 51.51, 52.28, 61.55, 69.33,78.64, 114.91, 115.18, 127.58, 128.90, 129.76, 129.89, 133.25, 135.25,137.70, 153.43, 153.71, 167.92, 170.91, 172.76. Anal Calcd forC₃₀H₃₆N₄O₆+0.2H₂O: C, 65.25; H, 6.64; N, 10.15; Found: C, 64.96; H,6.51; N, 10.11.

Step 4: To the CH₂Cl₂ solution (10 mL) of4-{4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester (0.37 g, 0.675 mmol), was added hydrogen chloridein ether solution (2.0 M, 1.6 mL, 8 mmol). The mixture was stirred atroom temperature overnight. The mixture was filtered. The resultingsolid was stirred with ether to give3-[1-oxo-4-(4-piperazin-1-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas white solid (240 mg, 69%). mp: 196-198° C.; HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1%H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R)=5.10 min (96%); ¹H NMR (DMSO-d₆) δ 1.90-2.07 (m, 1H, CHH),2.35-2.45 (m, 1H, CHH), 2.59 (d, J=15.7 Hz, 1H, CHH), 2.84-3.02 (m, 1H,CHH), 3.09-3.32 (b, 2H, CH₂), 3.41-3.51 (b, 4H, CH₂, CH₂), 4.22-4.53 (m,4H, CH₂, CH₂), 5.12 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.29 (s, 7H, CH₂),7.28-7.38 (m, 7H, Ar), 7.43-7.54 (m, 4H, Ar), 7.55-7.71 (m, 14H, Ar),10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 15.05, 22.32, 31.13, 45.02,47.29, 51.52, 68.94, 114.90, 115.31, 127.79, 129.78, 129.90, 131.44,133.30, 153.30, 167.89, 170.91, 172.76; LCMS MH=449. Anal Calcd forC₂₅H₂₈N₄O₄ 2.1HCl+1H₂O: C, 55.29; H, 5.96; N, 10.32; Cl, 13.71%; Found:C, 55.39; H, 6.13; N, 10.19; Cl: 13.61.

5.2203-{4-[4-(4-METHYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

4-Methylpiperidine (0.49 g, 4.94 mmol) was added to a stirred solutionor methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.71 g, 1.65 mmol) in DMF (15 mL) at 50° C. overnight. To the mixturewas added potassium carbonate (0.23 g, 1.65 mmol), and the mixture washeated at 90° C. overnight. The mixture was concentrated to give an oil,which was stirred in ethyl acetate (10 mL) overnight. The suspension wasfiltered to give a brown filtrate, which was evaporated and purified onsilica gel column with MeOH (solvent B)/dichloromethane (solvent A) aseluents to give3-{4-[4-(4-Methyl-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.22 g, 30% yield over 3 steps); HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in5 min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H3PO4), 5.16 min(98.1%); mp: 189-191° C.; 1H NMR (DMSO-d6) δ 0.88 (d, J=6.4 Hz, 3H,CH3), 1.04-1.20 (m, 2H, CHH), 1.23-1.41 (m, 1H, CHH), 1.49-1.63 (m, 2H,CH2), 1.81-2.04 (m, 3H, CH, CH2), 2.36-2.48 (m, 1H, CHH), 2.53-2.63 (m,1H, CHH), 2.69-2.82 (m, 2H, CH2), 2.83-2.99 (m, 1H, CHH), 3.38-3.52 (m,2H, CH2), 4.19-4.47 (m, 2H, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH),5.22 (s, 2H, CH2), 7.26-7.37 (m, 4H, Ar), 7.39-7.53 (m, 3H, Ar), 10.97(s, 1H, NH); 13C NMR (DMSO-d6) δ 21.79, 22.36, 30.23, 31.21, 33.89,45.10, 51.58, 53.22, 62.10, 69.44, 114.97, 115.23, 127.61, 128.86,129.81, 129.94, 133.31, 135.12, 153.51, 168.01, 170.96, 172.83; LCMSMH=462; Anal. Calcd for C₂₇H₃₁N₃O₄+0.1H2O: C, 69.99; H, 6.79; N, 9.07;Found: C, 69.84; H, 6.81; N, 9.12.

5.2213-{4-[4-(4-TERT-BUTYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1:4-Carbamoyl-4-[4-(4-chloromethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.63 g, 1.46 mmol) was added to a stirred solution of4-tert-butylpiperidine hydrochloride (0.78 g, 4.37 mmol) anddiisopropylethylamine (0.96 mL, 5.83 mmol) in DMF (15 mL) at 70° C. Themixture was heated for 5 hours and then evaporated and purified onsilica gel column (MeOH/CH₂Cl₂ gradient from 1% to 9% in 50 min) to give4-{4-[4-(4-tert-Butyl-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester as a light brown oily solid (1.23 g), which was usedin the next step without further purification.

Step 2: To a stirred solution of4-{4-[4-(4-tert-Butyl-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester in THF (15 ml) at room temperature was added potassiumtert-butoxide (0.33 g, 2.90 mmol). The mixture was stirred for 30minutes or until LCMS showed no starting material. The mixture wasquenched with 1 N HCl (2 ml) to give a clear brown solution and thenneutralized with saturated sodium bicarbonate (4 ml to pH=7). Themixture was extracted with ethyl acetate (2×30 mL), washed with brineand concentrated to a brown solid. It was purified on silica gel column(MeOH/CH₂Cl₂ gradient from 1% to 9% in 50 min) to give3-{4-[4-(4-tert-Butyl-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a light brown solid (0.56 g, 76% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄), 5.62 min(96.6%); mp: 208-210° C.; ¹H NMR (DMSO-d₆) δ 0.82 (s, 9H, 3CH₃),0.88-1.05 (m, 1H, CHH), 1.09-1.31 (m, 2H, CH₂), 1.49-1.65 (m, 2H, CH₂),1.83 (t, J=11.5 Hz, 2H, CH₂), 1.92-2.06 (m, 1H, CHH), 2.34-2.47 (m, 1H,CHH), 2.54-2.65 (m, 1H, CHH), 2.79-3.00 (m, 3H, CH, CH₂), 3.38-3.47 (m,2H, CH₂), 4.20-4.47 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH),5.22 (s, 2H, CH₂), 7.25-7.37 (m, 4H, Ar), 7.39-7.55 (m, 3H, Ar), 10.97(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.36, 26.44, 27.19, 31.21, 31.84,45.09, 45.94, 51.58, 53.98, 62.09, 69.45, 114.97, 115.21, 127.61,128.77, 129.81, 129.94, 133.31, 135.04, 138.64, 153.51, 168.01, 170.96,172.82; LCMS MH=504; Anal. Calcd for C₃₀H₃₇N₃O₄+0.1H₂O: C, 71.29; H,7.42; N, 8.31; Found: C, 70.96; H, 7.63; N, 8.32.

5.2223-{4-[4-(4-HYDROXY-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To a stirred colorless solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.51 g, 1.19 mmol) in acetonitrile (15 ml) was added piperidin-4-olhydrochloride (0.16 g, 1.19 mmol) and N-ethyl-N-isopropylpropan-2-amine(0.49 ml, 2.98 mmol). It was stirred at room temperature overnight. Tothe mixture was added piperidin-4-ol hydrochloride (0.09 g) and DIPEA(0.4 mL) and heated at 50° C. overnight. The mixture was purified onsilica gel column (MeOH/CH₂Cl₂ gradient from 1% to 9% in 50 minutes) togive4-carbamoyl-4-{4-[4-(4-hydroxy-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as an off-white solid (0.75 g, 78% yield).

Step 2: To a stirred solution of methyl5-amino-4-(4-(4-((4-hydroxypiperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.67 g, 1.35 mmol) in THF (30 ml) at room temperature, was addedpotassium 2-methylpropan-2-olate (0.61 g, 5.41 mmol). It was stirred forten minutes and then quenched with 1N HCl (2 ml), and neutralized bysaturated sodium bicarbonate (4 ml to pH=7). The mixture was extractedwith ethyl acetate (2×20 mL). The combined ethyl acetate phases werepurified on silica gel column (MeOH/CH₂Cl₂ gradient from 1% to 9% in 50min) to give3-{4-[4-(4-Hydroxy-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.24 g, 38% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5min, isocratic at 95/5 in 5 min (acetonitrile/0.1% H₃PO₄), 5.16 min(97.3%); mp: 204-206° C.; ¹H NMR (DMSO-d₆) δ 1.28-1.48 (m, 2H, CH₂),1.58-1.79 (m, 2H, CH₂), 1.89-2.15 (m, 3H, CHH, CH₂), 2.37-2.47 (m, 1H,CHH), 2.53-2.71 (m, 4H, CH₂, CHH, CHH), 2.83-2.99 (m, 1H, CHH),3.39-3.49 (m, 3H, CH₂, CHH), 4.21-4.47 (m, 2H, CH₂), 4.53 (d, J=4.2 Hz,1H, OH), 5.11 (dd, J=5.0, 13.1 Hz, 1H, NCH), 5.22 (s, 2H, CH₂),7.26-7.37 (m, 4H, Ar), 7.39-7.53 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.36, 31.21, 34.37, 45.10, 50.82, 51.58, 61.77, 66.26,69.44, 114.97, 115.21, 127.62, 128.80, 129.81, 129.95, 133.31, 135.10,138.58, 153.51, 168.01, 170.98, 172.83; LCMS MH=464; Anal. Calcd forC₂₆H₂₉N₃O₅+0.5H₂O: C, 66.09; H, 6.40; N, 8.89; Found: C, 65.95; H, 6.31;N, 8.74.

5.2233-{4[4-(4-ETHOXYMETHYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: To a stirred solution of methyl5-amino-4-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.67 g, 1.54 mmol) in acetonitrile (15 ml) in an ice bath, was added4-(ethoxymethyl)piperidine (0.44 g, 3.09 mmol). It was stirred at roomtemperature for half an hour, followed by addition of one equivalent ofDIPEA (0.26 mL), and the solution was stirred at room temperatureovernight. To the reaction mixture were added 0.17 g of4-(ethoxymethyl)piperidine and 0.30 mL of DIPE. The mixture was heatedat 70° C. for three hours and then cooled to room temperature. Thesolution was evaporated to an oil, which was purified on silica gelcolumn (MeOH/CH₂Cl₂ gradient from 1% to 9% in 50 min) to give4-carbamoyl-4-{4-[4-(4-ethoxymethyl-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as a foamy solid, which was used in the next stepwithout further purification.

Step 2: To a stirred solution of methyl5-amino-4-(4-(4-((4-(ethoxymethyl)piperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.83 g, 1.54 mmol) in THF (10 ml) in an ice bath, was added potassium2-methylpropan-2-olate (0.52 g, 6.18 mmol). The mixture was stirred forten minutes and quenched with 1 N HCl (4 mL) to form clear solution thenneutralized with saturated sodium bicarbonate (7 ml to pH=8). Theresulting mixture was extracted with ethyl acetate (2×20 mL) andpurified on silica gel column (MeOH/CH₂Cl₂ gradient from 1% to 9% in 50min) to give3-{4-[4-(4-ethoxymethyl-piperidin-1-ylmethyl)-benzyloxy]-1-oxo1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione as a white solid (0.45g, 58% yield); HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min,240 nm, gradient from 10/90 to 95/5 in 5 min, isocratic at 95/5 in 5 min(acetonitrile/0.1% H₃PO₄), 5.38 min (96.7%); mp: 168-170° C.; ¹H NMR(DMSO-d₆) δ 1.08 (t, J=7.0 Hz, 3H, CH₃), 1.12-1.23 (m, 2H, CH₂),1.40-1.54 (m, 1H, CHH), 1.55-1.67 (m, 2H, CH₂), 1.81-2.04 (m, 3H, CHH,CH₂), 2.36-2.48 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.72-2.82 (m, 2H,CH₂), 2.84-2.99 (m, 1H, CHH), 3.19 (d, J=6.2 Hz, 2H, CH₂), 3.34-3.48 (m,4H, CH₂, CH₂), 4.19-4.47 (m, 2H, CH₂), 5.11 (dd, J=5.2, 13.3 Hz, 1H,NCH), 5.22 (s, 2H, CH₂), 7.26-7.37 (m, 4H, Ar), 7.39-7.54 (m, 3H, Ar),10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 15.10, 22.36, 28.92, 31.20,35.80, 45.10, 51.58, 52.93, 62.19, 65.44, 69.45, 74.83, 114.97, 115.23,127.61, 128.80, 129.81, 129.95, 133.31, 135.07, 138.64, 153.53, 168.01,170.98, 172.83; LCMS MH=506; Anal. Calcd for C₂₉H₃₅N₃O₅+0.5H₂O: C,67.68; H, 7.05; N, 8.17; Found: C, 67.42; H, 7.20; N, 8.05.

5.2243-(1-OXO-4-(4-((4-(TRIFLUOROMETHYL)PIPERIDIN-1-YL)METHYL)BENZYLOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: tert-Butyl5-amino-5-oxo-2-(1-oxo-4-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)benzyloxy)isoindolin-2-yl)pentanoate

To a solution of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(450 mg, 0.95 mmol) and N,N-diisopropylethylamine (0.42 mL, 2.38 mmol)in MeCN (9 mL), was added 4-(trifluoromethyl)piperidine hydrochloride(271 mg, 1.43 mmol). The mixture was stirred for 5 h at 60° C. The crudemixture was partitioned between EtOAc (150 mL) and 1N NaHCO₃ (30 mL).The basic aq layer was washed with additional EtOAc (˜100 mL). Theorganic layers were combined, washed with brine, dried (Na₂SO₄), andconcentrated in vacuo to give tert-butyl5-amino-5-oxo-2-(1-oxo-4-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)benzyloxy)isoindolin-2-yl)pentanoateas an oil (570 mg). LC/MS M+H=590. The crude product was used in thenext step without further purification.

Step 2:3-(1-Oxo-4-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dione

To a cooled solution of tert-butyl5-amino-5-oxo-2-(1-oxo-4-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)benzyloxy)isoindolin-2-yl)pentanoate(561 mg, 0.95 mmol) in THF (10 mL) in an ice bath, was added KO^(t)Bu(128 mg, 1.14 mmol) as a solid in one portion. The ice bath was removedand the reaction mixture was stirred for-2 h at room temperature. MoreKO^(t)Bu (28 mg) was added and the reaction mixture was stirred for ˜2h. The reaction mixture was cooled in an ice bath and quenched withacetic acid (0.163 mL, 2.85 mmol). The mixture was concentrated in vacuoand the resulting solid was partitioned between EtOAc (100 mL) and 1NNaHCO₃ (30 mL). The aq. layer was extracted with EtOAc (50 mL), and thecombined organic layer was washed with brine, dried (Na₂SO₄), andconcentrated in vacuo to give a white solid (˜400 mg). The solid wastriturated with Et₂O (40 mL) with the aid of sonication, collected byfiltration, and washed with additional Et₂O. The solid was suction driedand a second trituration was carried out using water (120 mL). Theremaining solid was suction dried and then dried in vacuum oven at 40°C. overnight to give3-(1-oxo-4-(4-((4-(trifluoromethyl)piperidin-1-yl)methyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (328 mg, 67% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 6.16 min (96.5%);mp: 178-180° C.; ¹H NMR (DMSO-d₆) δ 1.34-1.55 (m, 2H, CHH, CHH),1.66-1.82 (m, 2H, CHH, CHH), 1.87-2.05 (m, 3H, CHH, CHH, CHH),2.14-2.35-(m, 1H, CHH), 2.35-2.48 (m, 1H, CHH), 2.52-2.65 (m, 1H, CHH),2.78-3.00 (m, 3H, CHH, CHH, CHH), 3.48 (s, 2H, CH₂), 4.25 (d, J=17.6 Hz,1H, CHH), 4.42 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.3 Hz, 1H,CHH), 5.17-5.28 (m, 2H, CH₂), 7.21-7.39 (m, 4H, Ar), 7.39-7.55 (m, 3H,Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.33, 24.19, 31.18, 38.35,39.07, 45.06, 51.39, 51.55, 61.59, 69.39, 114.96, 115.20, 127.64, 127.82(q, J=278 Hz, CF₃), 128.79, 129.80, 129.93, 133.30, 135.22, 138.11,153.49, 167.99, 170.96, 172.81; Part of quartet (2 signals) arising fromCF₃C are masked by DMSO peak around δ 40 ppm. LC/MS M+H=516; Anal Calcdfor C₂₇H₂₈F₃N₃O₄+0.35H₂O: C, 62.15; H, 5.54; N, 8.05; F, 10.92; Found:C, 62.13; H, 5.48; N, 8.06; F, 9.84.

5.2253-(4-(4-(((2R,6S)-2,6-DIMETHYLPIPERAZIN-1-YL)METHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: To a solution of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(400 mg, 0.846 mmol) in acetonitrile (10 ml) were added(3R,5S)-tert-butyl 3,5-dimethylpiperazine-1-carboxylate (236 mg, 1.099mmol), N,N-Diisopropylethylamine (328 mg, 2.54 mmol) and sodium iodide(25 mg, 0.17 mmol). The formed mixture was heated at 70° C. for 2 days.The reaction mixture was concentrated, the residue was partitionedbetween ethyl acetate (50 ml) and aqueous saturated sodium bicarbonate(10 ml), the organic layer was washed with water, brine and dried overMgSO₄, and the solvent was evaporated under vacuum, the residue waspurified by ISCO (40 g column, MeOH/CH₂Cl₂ gradient from 0% to 5% in 50min) to give (3R,5 S)-tert-butyl4-(4-((2-(5-amino-1-tert-butoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)-3,5-dimethylpiperazine-1-carboxylate(480 mg, 87% yield).

Step 2: To a mixture of (3R,5S)-tert-butyl4-(4-((2-(5-amino-1-tert-butoxy-1,5-dioxopent-an-2-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)-3,5-dimethylpiperazine-1-carboxylate(480 mg, 0.738 mmol) in THF was added potassium tert-butoxide (83 mg,0.738 mmol) at 0° C. The mixture was stirred at 0° C. for 10 minutes,warmed up to room temperature and stirred for 4 hours. Additionalpotassium tert-butoxide (25 mg, 0.22 mmol) was added and the mixture wasstirred for another 2 hours. The reaction was quenched with acetic acid(0.2 ml), THF was evaporated, and the residue was partitioned betweenethyl acetate (100 ml) and aqueous saturated sodium bicarbonate (10 ml).The organic phase was washed with brine, dried over MgSO₄. The solventwas removed and the residue was purified by ISCO (40 g column,MeOH/CH₂Cl₂ gradient from 0% to 5% in 50 min) to give (3R,5S)-tert-butyl4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)-3,5-dimethylpiperazine-1-carboxylate(120 mg, 28% yield); ¹H NMR (DMSO-d₆) δ 0.94 (d, J=6.0 Hz, 6H, CH₃,CH₃), 1.38 (s, 9H, CH₃, CH₃, CH₃), 1.84-2.11 (m, 1H, CHH), 2.36-2.49 (m,3H, CHH, CH₂), 2.52-2.75 (m, 3H, CHH, CH₂), 2.81-3.06 (m, 1H, CHH),3.62-3.80 (m, 4H, CH₂, CH, CH), 4.18-4.51 (m, 2H, CH₂), 5.06-5.16 (m,1H, CH), 5.18-5.26 (m, 2H, CH₂), 7.29-7.52 (m, 7H, Ar), 10.84-11.10 (m,1H, NH).

Step 3: To the mixture of (3R,5S)-tert-butyl4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)-3,5-dimethylpiperazine-1-carboxylate(120 mg, 0.208 mm-ol) in dicloromethane (40 mL) was added HCl solutionin ether (2 N, 5 ml, 10 mmol), The mixture was stirred at roomtemperature for 2 days. The formed precipitate was separated byfiltration to give3-(4-(4-(((2R,6S)-2,6-dimethylpiperazin-1-yl)methyl)-benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (80 mg, 75% yield); mp: 253-255° C.; ¹H NMR (DMSO-d₆) δ1.16-1.40 (m, 6H, CH₃, CH₃), 1.97 (d, J=5.3 Hz, 1H, CHH), 2.24-2.43 (m,1H, CHH), 2.58 (d, J=2.1 Hz, 1H, CHH), 2.71-3.06 (m, 3H, CH₂, CHH),3.07-3.59 (m, 4H, CH₂, CH, CH), 4.04-4.54 (m, 4H, CH₂, CH₂), 5.02 (dd,J=5.1, 13.2 Hz, 1H, CH), 5.22 (s, 2H, CH₂), 7.21-7.34 (m, 2H, Ar),7.38-7.56 (m, 5H, Ar); ¹³C NMR (DMSO-d₆) δ 15.82, 22.27, 31.03, 38.23,45.25, 45.90, 50.32, 51.69, 68.96, 115.10, 115.39, 127.82, 129.70,129.86, 129.97, 133.11, 136.86, 153.24, 168.25, 170.87, 172.94; LCMSMH-2HCl=477; HPLC: Waters Xterra C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240nm, Gradient (CH₃CN/0.1% HCOONH₄) 5/95 to 95/5 in 5 min, 95/5 10 min:t_(R)=4.21 (100%); Anal. Calcd for C₂₇H₃₄N₄O₄Cl₂+0.9H₂O: C, 57.33; H,6.38; N, 9.90; Found: C, 57.36; H, 6.36; N, 9.80.

5.2263-(1-OXO-4-(4-((3-OXOPIPERAZIN-1-YL)METHYL)BENZYLOXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a suspension of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy-1-oxoisoindolin-2-yl)-5-oxopentanoate(450 mg, 0.951 mmol, preparation described herein) in MeCN (9 mL) wasadded piperazin-2-one (191 mg, 1.903 mmol) and N,N-diisopropylethylamine(0.249 mL, 1.427 mmol). The mixture was warmed up to 60° C. and stirredfor ˜18 h and then allowed to cool to room temperature. A solid formedupon cooling which was dispersed by addition of DMF (3 mL) andsonication. The mixture was cooled in ice bath and solid KO^(t)Bu (299mg, 2.66 mmol) was added in one portion. Dry THF(2 mL) was added and theice bath was removed. The mixture was stirred at room temperatureovernight. The mixture was cooled to 0° C. in an ice bath and thenquenched with acetic acid (254 μl, 4.44 mmol). The mixture wasconcentrated in vacuo and the oily residue was partitioned between EtOAc(200 mL) and 1N NaHCO₃ (40 mL). The product partitioned in both aqueousand organic layers. All layers were combined, acidified with HCl, andconcentrated to give a solid. The solid was triturated with copious DMF,the mixture was filtered, and the undissolved solids were washed withadditional DMF (total filtrate volume˜150 mL). The filtrate wasconcentrated to an oily residue which was redissolved in DMF/1 N HCl (6mL/4 mL) and then purified by injection onto a C-18 preparatory HPLCcolumn. The product was eluted with an acetonitrile/water gradient (0.1%formic acid in both mobile phases, 5% to 30% MeCN over 20 minutes) andfractions were collected by mass trigger. The desired fractions werecombined and concentrated in vacuo to give3-(1-oxo-4-(4-((3-oxopiperazin-1-yl)methyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dioneas an off-white solid (177 mg, 43% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 4.58 min(98.3%); mp: 245-247° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.04 (m, 1H, CHH),2.35-2.48 (m, 1H, CHH), 2.51-2.63 (m, 3H, CHH, CH₂), 2.80-2.99 (m, 3H,CHH, CH₂), 3.06-3.23 (m, 2H, CH₂), 3.54 (s, 2H, CH₂), 4.25 (d, J=17.6Hz, 1H, CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz,1H, CH), 5.24 (s, 2H, CH₂), 7.21-7.39 (m, 4H, Ar), 7.41-7.56 (m, 3H,Ar), 7.74 (s, 1H, NH), 10.96 (br. s., 1H, NH); ¹³C NMR (DMSO-d₆) 22.33,31.16, 45.07, 48.35, 51.55, 56.62, 60.40, 69.38, 114.97, 115.22, 127.70,128.91, 129.80, 129.95, 133.30, 135.49, 137.28, 153.48, 167.56, 167.99,170.96, 172.81; LC/MS M+H=463; Anal Calcd for C₂₅H₂₆N₄O₅: C, 64.92; H,5.67; N, 12.11; Found: C, 61.40; H, 5.38; N, 11.45.

5.2273-{4-[4-(4-DIMETHYLAMINO-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: Preparation of4-Carbamoyl-4-{4-[4-(4-isopropyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester

To a solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.674 g, 1.418 mmol) in acetonitrile (15 ml) at room temperature wasadded N,N-dimethylpiperidin-4-amine (0.545 g, 4.25 mmol). The mixturewas stirred for ten minutes and was evaporated to give an oil. It wasstirred in methylene chloride (30 ml) and water (10 ml). The methylenechloride phase was separated and evaporated to give4-Carbamoyl-4-{4-[4-(4-isopropyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as ao oil (0.76 g, 103% crude yield). It was used inthe next step without further purification.

Step 2: Preparation of3-{4-[4-(4-Dimethylamino-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To a stirred solution of methyl5-amino-4-(4-(4-((4-(dimethylamino)piperidin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.76 g, 1.454 mmol) in THF (20 ml) in an ice-bath was added potassium2-methylpropan-2-olate (0.32 g, 2.90 mmol). The mixture was stirred forten minutes and 1 N HCl (2 ml to pH=3) was added, then neutralized bysaturated sodium bicarbonate (4 ml to pH=7). The mixture was stirredwith ethyl acetate (50 ml). The organic phase was separated and washedwith brine (20 ml) to and concentrated to give an off-white solid. Itwas stirred in acetonitrile (4 ml) at 70° C. for half hour and filteredto give3-{4-[4-(4-Dimethylamino-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.18 g, 25% yield); mp 209-211° C.; ¹H NMR (DMSO-d₆) δ1.35 (qd, J=3.8, 11.8 Hz, 2H, CH₂), 1.61-1.76 (m, 2H, CH₂), 1.82-2.08(m, 4H, CH₂, CHH, CH), 2.14 (s, 6H, 2CH₃), 2.34-2.47 (m, 1H, CHH),2.53-2.64 (m, 1H, CHH), 2.74-3.01 (m, 3H, CH₂, CHH), 3.43 (s, 2H, CH₂),4.19-4.49 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H,CH₂), 7.27-7.37 (m, 4H, Ar), 7.39-7.54 (m, 3H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.36, 28.05, 31.21, 41.49, 45.09, 51.58, 52.41,61.61, 61.80, 69.45, 114.97, 115.21, 127.62, 128.77, 129.81, 129.95,133.31, 135.09, 138.58, 153.51, 168.01, 170.96, 172.82. LC/MS(M+1)⁺=491; Anal Calcd for C₂₈H₃₄N₄O₄+0.2H₂O: C, 68.05; H, 7.02; N,11.34; Found: C, 67.88; H, 6.88; N, 11.19.

5.2283-{4-[4-(4-ISOPROPYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the acetonitrile solution of the mixture (˜1:1) of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.25 g, 0.564 mmol) and3-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.225 g, 0.564 mmol) was added N-ethyl-N-isopropylpropan-2-amine (0.292g, 2.256 mmol) followed by 1-isopropylpiperazine (0.174 g, 1.354 mmol)at room temperature. The cloudy mixture was stirred at room temperatureovernight. The white suspension was evaporated under vacuum to get ridof acetonitrile. The resulting white solid was stirred in water (40 ml)and methylene chloride (2×40 ml). The combined methylene chloride phaseswere back washed with water (50 ml) and then evaporated in vacuo to givea white oily solid, which was stirred in diethyl ether (25 ml)overnight. The suspension was filtered to give an off-white solid, whichwas mixed with acetonitrile (4 ml) and stirred in a 50° C. oil bath forhalf hour then the suspension was filtered to give3-{4-[4-(4-Isopropyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.187 g, 34% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 3.94 min (95.8%);mp, 193-195° C.; ¹H NMR (DMSO-d₆) δ 0.94 (d, J=6.4 Hz, 6H, 2CH₃),1.91-2.04 (m, 1H, CHH), 2.21-2.48 (m, 9H, 4CH₂, CH), 2.53-2.67 (m, 2H,CHH, CHH), 2.82-2.99 (m, 1H, CHH), 3.44 (s, 2H, CH₂), 4.20-4.47 (m, 2H,CH₂), 5.11 (dd, J=5.2, 13.1 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.26-7.36(m, 4H, Ar), 7.38-7.54 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆)δ 18.22, 22.36, 31.21, 45.09, 47.95, 51.58, 53.04, 53.55, 61.81, 69.44,114.97, 115.23, 127.62, 128.86, 129.81, 129.95, 133.31, 135.13, 138.24,153.51, 168.01, 170.98, 172.83. Anal Calcd for C₂₈H₃₄N₄O₄+0.1H₂O: C,68.30; H, 7.00; N, 11.38. Found: C, 68.21; H, 6.61; N, 11.19.

5.2293-{1-OXO-4-[4-(4-PHENYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN solution (15 ml) of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.50 g, 1.13 mmol) and was added N-ethyl-N-isopropylpropan-2-amine(0.373 ml, 2.256 mmol) followed by 1-phenylpiperazine (0.257 ml, 1.692mmol) at room temperature. The cloudy mixture was stirred at roomtemperature overnight. Solvent was evaporated and the resulting whitesolid was stirred in water (50 ml) and extracted with methylene chloride(2×80 ml). The combined methylene chloride phases were back washed withwater (50 ml), brine (30 ml) and evaporated to a white solid which wasstirred in acetonitrile (8 ml) at 50° C. for one hour then filtered,dried in vacuum oven to give3-{1-Oxo-4-[4-(4-phenyl-piperazin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.316 g, 53% yield); mp, 195-197° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 4.70min (95.43%). ¹H NMR (DMSO-d6) δ 1.92-2.06 (m, 1H, CHH), 2.36-2.47 (m,1H, CHH), 2.53-2.65 (m, 2H, CHH, CHH), 2.83-2.99 (m, 1H, CHH), 3.12 (t,J=5.1 Hz, 4H, CH₂, CH₂), 3.50-3.62 (m, 2H, CH₂), 4.20-4.48 (m, 2H, CH₂),5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.20-5.30 (m, 2H, CH₂), 6.76 (t,J=7.3 Hz, 1H, Ar), 6.91 (d, J=7.9 Hz, 2H, Ar), 7.15-7.25 (m, 2H, Ar),7.28-7.41 (m, 4H, Ar), 7.42-7.55 (m, 3H, Ar), 10.98 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.36, 31.21, 45.09, 48.18, 51.58, 52.52, 61.71, 69.41,114.97, 115.24, 115.35, 118.76, 127.68, 128.86, 129.01, 129.82, 129.95,133.32, 135.30, 137.93, 150.98, 153.50, 168.01, 170.98, 172.83. LC/MS(M+1)⁺=525; Anal Calcd for C₃₁H₃₂N₄O₄: C, 70.97; H, 6.15; N, 10.68;Found: C, 70.69; H, 6.01; N, 10.49.

5.230 3-{4-[4-(4-CYCLOPROPANESULFONYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: 4-Cyclopropanesulfonyl-piperazine-1-carboxylic acid tert-butylester

To the stirred solution of tert-butyl piperazine-1-carboxylate (1.3 g,6.98 mmol) in DCM anhydrous (10 mL) was added TEA (1.167 ml, 8.38 mmol)and cyclopropanesulfonyl chloride (1.079 g, 7.68 mmol) at roomtemperature. White solid was formed and the mixture wad stirred for 2hrs. The reaction mixture was diluted by DCM (40 mL) and washed withwater (25 mL). Organic layer was dried by MgSO₄ and concentrated to give4-Cyclopropanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester asa white solid (2.3 g, 113% crude yield). The compound was used in thenext step without further purification. LCMS MH=291.

Step 2: 1-(Cyclopropylsulfonyl)Piperazine Hydrochloride

To the stirred solution of tert-butyl4-(Cyclopropylsulfonyl)piperazine-1-carboxylate (2.3 g, 7.92 mmol) inDCM (Volume: 10 ml) at room temperature was added HCl in ether (11.88ml, 23.76 mmol). The reaction mixture was stirred at room temperaturefor 22 hrs and solid was formed during the reaction. The suspension wasadded by diethyl ether (20 mL) and stirred for 10 mins before it wasfiltered. The white solid was washed with diethyl ether (2×15 mL) anddried under suction to give 1-(cyclopropylsulfonyl)piperazinehydrochloride as a solid (1.51 g, 84% yield); LCMS MH=191; ¹H NMR(DMSO-d₆) δ 0.85-1.09 (m, 4H, CH₂, CH₂), 2.63-2.81 (m, 1H, CH),3.06-3.23 (m, 4H, CH₂, CH₂), 3.33-3.57 (m, 4H, CH₂, CH₂), 9.54 (br. s.,2H, NH₂Cl).

Step 3:3-{4-[4-(4-Cyclopropanesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred suspension of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300 mg, 0.677 mmol) and 1-(cyclopropylsulfonyl)piperazine hydrochloride(230 mg, 1.015 mmol) in Acetonitrile (Volume: 10 ml) at room temperaturewas added DIPEA (0.355 ml, 2.030 mmol). The suspension turned to beclear and the resulting mixture was stirred at room temperature forfurther reaction. The reaction mixture was stirred at room temperaturefor 20 hrs before it was added by EtOAc (50 mL) and NaHCO₃ (aq, sat, 20mL). The mixture was extracted and the organic layer was dried by MgSO₄.The organic layer was concentrated and the residue was purified by slicagel chromatography to give3-{4-[4-(4-Cyclopropanesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (227 mg, 61% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80, CH₃CN/0.1% H₃PO₄), 4.09 min(99.9%); m.p. 145-147° C.; ¹H NMR (DMSO-d₆) δ 0.86-1.05 (m, 4H, CH₂,CH₂), 1.91-2.04 (m, 1H, CHH), 2.34-2.47 (m, 5H, CH₂, CH₂, CHH),2.53-2.66 (m, 2H, CHH, CH), 2.81-3.01 (m, 1H, CHH), 3.11-3.24 (m, 4H,CH₂, CH₂), 3.52 (s, 2H, CH₂), 4.25 (d, J=17.6 Hz, 1H, CHH), 4.42 (d,J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.23 (s, 2H,CH₂), 7.27-7.38 (m, 4H, Ar), 7.40-7.56 (m, 3H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 3.75, 22.34, 24.46, 31.16, 45.06, 45.80, 51.55,51.85, 61.20, 69.35, 114.94, 115.22, 127.67, 128.90, 129.80, 129.93,133.28, 135.37, 137.69, 153.46, 167.97, 170.96, 172.81; LCMS MH=553;Anal. Calcd for C₂₈H₃₂N₄O₆S+.5H₂O+0.15CH₂Cl₂: C, 58.86; H, 5.84; N,9.75; Found: C, 58.53; H, 5.47; N, 9.57.

5.2313-{4-[4-(4-CYCLOHEXANESULFONYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: 4-Cyclohexanesulfonyl-piperazine-1-carboxylic acid tert-butylester

To the stirred solution of tert-butyl piperazine-1-carboxylate (450 mg,2.416 mmol) in DCM anhydrous (10 mL) was added cyclohexanesulfonylchloride (485 mg, 2.66 mmol) and triethylamine (0.370 ml, 2.66 mmol).The resulting solution was stirred at room temperature for 20 mins andthe reaction was completed. The reaction was complete. The reactionmixture was diluted by DCM (40 mL) and the mixture was washed by water(20 mL) and brine (20 mL). The mixture was extracted and organic layerwas dried by MgSO₄ and concentrated under vacuo to give4-Cyclohexanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester as aoff white solid (750 mg, 93% crude yield). The compound was put to nextstep without further purification; LCMS MH (without boc group)=233.

Step 2: 1-Cyclohexanesulfonyl-piperazine hydrocloride

To the solution of tert-butyl4-(cyclohexylsulfonyl)piperazine-1-carboxylate (750 mg, 2.256 mmol) inDCM (5 mL) was added HCl (2M in ether, 5 mL, 10.00 mmol) and diethylether (5.0 mL). The resulting solution was stirred at room temperaturefor 4 days and was concentrated under vacuo. The residue was added byHCl (2M in ether, 15 mL) and the resulting suspension was stirred atroom temperature over night and the reaction was completed. The reactionmixture was filtered and the solid was washed with ether (2×15 mL) togive 1-Cyclohexanesulfonyl-piperazine hydrochloride as an off whitesolid (450 mg, 74% yield). and HNMR were tested for the compound. ¹H NMR(DMSO-d₆) δ 1.03-1.45 (m, 5H, CH₂, CH₂, CH), 1.54-1.69 (m, 1H, CH),1.70-1.84 (m, 2H, CH₂), 1.90-2.05 (m, 2H, CH₂), 3.03-3.16 (m, 4H, CH₂,CH₂), 3.17-3.28 (m, 1H, CHH), 3.41-3.57 (m, 4H, CH₂, CH₂), 9.42 (br. s.,2H, NH₂Cl); LCMS MH=233.

Step 3:3-{4-[4-(4-Cyclohexanesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred suspension of 1-(cyclohexylsulfonyl)piperazinehydrochloride (273 mg, 1.01 mmol) in Acetonitrile (8 mL) at roomtemperature was added DIPEA (0.36 ml, 2.03 mmol). The suspension becameclear solution immediately. And to the clear solution was added3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300 mg, 0.68 mmol). The resulting mixture was stirred at roomtemperature for 20 hrs. The reaction mixture was added by EtOAc (50 mL)and NaHCO₃ (sat. aq. 20 mL). The mixture was extracted and the organiclayer was dried by MgSO₄. The organic layer was concentrated and theresidue was purified by ISCO to gave3-{4-[4-(4-Cyclohexanesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (150 mg, 37% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75, CH₃CN/0.1% H₃PO₄), 5.03 min(99.9%); mp: 245-247° C.; ¹H NMR (DMSO-d₆) δ 1.03-1.21 (m, 1H, CHH),1.21-1.45 (m, 4H, CH₂, CH₂), 1.59 (br. s., 1H, CHH), 1.78 (br. s., 2H,CH₂), 1.97 (d, J=7.6 Hz, 3H, CHH, CH₂), 2.32-2.47 (m, 5H, CHH, CH₂,CH₂), 2.53-2.65 (m, 1H, CHH), 2.82-3.00 (m, 1H, CHH), 3.09 (t, J=11.4Hz, 1H, CH), 3.17-3.28 (m, 4H, CH₂, CH₂), 3.51 (s, 2H, CH₂), 4.18-4.32(m, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1,13.2 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 7.33 (d, J=7.6 Hz, 4H, Ar),7.40-7.56 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.34,24.43, 24.75, 26.18, 31.16, 45.06, 45.52, 51.55, 52.54, 59.29, 61.31,69.35, 114.96, 115.22, 127.64, 128.92, 129.80, 129.93, 133.28, 135.35,137.64, 153.48, 167.97, 170.96, 172.81; LCMS MH=595; Anal. Calcd forC₃₁H₃₈N₄O₆S: C, 62.61; H, 6.44; N, 9.42; Found: C, 62.63; H, 6.21; N,9.56.

5.2323-(4-((4-((4-(METHYLSULFONYL)PIPERIDIN-1-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a clear solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.451 mmol) in ACETONITRILE (5 mL, 96 mmol), was added4-(methylsulfonyl)piperidine (110 mg, 0.677 mmol) and the resultingslurry was stirred at room temperature overnight. The reaction mixturewas diluted with EtOAc (10 mL), stirred for 5 min, then filtered. Thesolid was washed with EtOAc (2 mL) and water (2 mL) and dried further invaccum oven at 50° C. to gave3-(4-((4-((4-(methylsulfonyl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (140 mg, 59% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 17/83 CH₃CN/0.1% H₃PO₄, 3.92 min (98.2%);mp: 1.73-175° C.; ¹H NMR (DMSO-d₆) δ 1.47-1.69 (m, 2H, CHH, CHH),1.84-2.07 (m, 5H, CHH, CHH, CHH, CHH, CHH), 2.35-2.48 (m, 1H, CHH),2.53-2.63 (m, 1H, CHH), 2.83-2.97 (m, 6H, CHH, CHH, CHH, CH₃), 2.98-3.11(m, 1H, CH), 3.49 (s, 2H, CH₂), 4.25 (d, J=17.4 Hz, 1H, CHH), 4.42 (d,J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CH), 5.23 (s, 2H,CH₂), 7.33 (d, J=7.2 Hz, 4H, Ar), 7.41-7.55 (m, 3H, Ar), 10.97 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 22.26, 24.34, 31.09, 37.25, 44.99, 51.38,51.48, 58.64, 61.29, 69.31, 114.90, 115.15, 127.57, 128.71, 129.73,129.86, 133.23, 135.17, 138.03, 153.41, 167.90, 170.89, 172.74; LCMS:MH=526; Anal Calcd for C₂₇H₃₁N₃O₆S+0.4H₂O: C, 60.86; H, 6.02; N, 7.89;S, 6.02; Found: C, 60.79; H, 5.77; N, 7.78; S, 5.82.

5.233 3-{4-[4-(4-CYCLOHEXANECARBONYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: 4-Cyclohexanecarbonyl-piperazine-1-carboxylic acid tert-butylester

To the stirred solution of tert-butyl piperazine-1-carboxylate (1.207 g,6.48 mmol) in DCM (Volume: 15 ml) was added cyclohexanecarbonyl chloride(1 g, 6.82 mmol) and DIPEA (1.187 ml, 6.82 mmol). The resulting solutionwas stirred at room temperature for 1.5 hrs before it was diluted by DCM(20 mL). The mixture was washed with water (20 mL) and brine (20 mL)respectively. Organic layer was dried by MgSO₄ and concentrated undervacuo to give 4-Cyclohexanecarbonyl-piperazine-1-carboxylic acidtert-butyl ester as a white solid (1.92 g, 95% crude yield); LCMSMH=296.

Step 2: Cyclohexyl(piperazin-1-yl)methanone hydrochloride

The suspension of tert-butyl4-(cyclohexanecarbonyl)piperazine-1-carboxylate (1.92 g, 6.48 mmol) inHCl (2M in ether, 25 mL) was stirred at room temperature over weekendand filtered. The white solid was washed with diethyl ether (15 mL×2)and dried under suction to give cyclohexyl(piperazin-1-yl)methanonehydrochloride (1.5 g, 99% crude yield). ¹H NMR (DMSO-d6) δ 0.99-1.46 (m,5H, CH₂, CH₂, CHH), 1.52-1.82 (m, 5H, CH₂, CH₂, CHH), 2.54-2.68 (m, 1H,CHH), 2.85-3.19 (m, 4H, CH₂, CH₂), 3.53-3.94 (m, 4H, CH₂, CH₂), 9.52(br. s., 2H, NHHCl); LCMS MH=197.

Step 3:3-{4-[4-(4-Cyclohexanecarbonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred mixture of cyclohexyl(piperazin-1-yl)methanonehydrochloride (239 mg, 1.03 mmol) in Acetonitrile (10 mL) was addedDIPEA (0.345 ml, 1.97 mmol) followed by the addition of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.79 mmol) and stirred at room temperature overnight. Thereaction mixture was diluted by EtOAc (70 mL) and washed with NaHCO₃(aq, sat. 25 mL) and brine (15 mL). Organic layer was dried by MgSO₄ andfiltered. The filtrate was concentrated uncer vacuo and the residue waspurified by ISCO chromatography to give3-{4-[4-(4-Cyclohexanecarbonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (271 mg, 61% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 m, 1 mL/min, 240 nm, 25/75, (CH₃CN/0.1% H₃PO₄), 3.18 min(98.9%); mp: 215-217° C.; ¹H NMR (DMSO-d₆) δ 1.05-1.41 (m, 5H, CH₂, CH₂,CHH), 1.52-1.76 (m, 5H, CH₂, CH₂, CHH), 1.91-2.05 (m, 1H, CHH),2.21-2.40 (m, 5H, CHH, CH₂, CH₂), 2.60 (br. s., 2H, CHH, CHH), 2.82-3.01(m, 1H, CHH), 3.37-3.54 (m, 6H, CH₂, CH₂, CH₂), 4.26 (d, J=17.4 Hz, 1H,CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH),5.23 (s, 2H, CH₂), 7.33 (d, J=7.4 Hz, 4H, Ar), 7.38-7.55 (m, 3H, Ar),10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.34, 25.10, 25.52, 29.08,31.18, 44.74, 45.06, 51.55, 52.36, 53.18, 61.50, 69.36, 114.94, 115.20,127.63, 128.97, 129.78, 129.93, 133.28, 135.31, 137.70, 153.46, 167.97,170.96, 172.81, 173.22; LCMS MH=559; Anal. Calcd for C₃₂H₃₈N₄O₅+0.2H₂O:C, 68.36; H, 6.88; N, 9.96; Found: C, 68.39; H, 6.75; N, 9.89.

5.2343-{4-[4-(4-BENZOYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To a stirred solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.422 g, 0.952 mmol) in acetonitrile (10 ml) at room temperature wasadded phenyl(piperazin-1-yl)methanone hydrochloride (0.324 g, 1.428mmol) and N-ethyl-N-isopropylpropan-2-amine (0.472 ml, 2.86 mmol). Themixture was stirred at room temperature overnight. Solvent wasevaporated and the resulting solid was stirred in water (30 ml) andmethylene chloride (50 ml). The org phase was washed with saturatedsodium bicarbonate (2×20 ml), brine (20 ml), dried and concentrated to alight yellow foamy solid (0.55 g) and stirred in diethyl ether (15 ml)at room temperature overnight. The ether suspension was filtered andstirred in acetonitrile (8 ml) at 55° C. for one hour then cooled andfiltered to give3-{4-[4-(4-Benzoyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.258 g, 49% yield); mp, 194-196° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 4.67min (95.3%). ¹H NMR (DMSO-d₆) δ 1.90-2.05 (m, 1H, CHH), 2.23-2.48 (m,5H, 2CH₂, CHH), 2.57 (d, J=14.9 Hz, 1H, CHH), 2.81-3.01 (m, 1H, CHH),3.18-3.44 (m, 3H, CH₂, CH), 3.55-3.77 (m, 1H, CH), 4.18-4.48 (m, 2H,CH₂), 5.11 (dd, J=5.2, 13.3 Hz, 1H, NCH), 5.17-5.28 (m, 2H, CH₂),7.25-7.54 (m, 12H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.36,31.20, 45.09, 41.53, 47.14, 51.58, 52.58, 61.51, 69.38, 114.97, 115.23,126.85, 127.68, 127.90, 128.38, 128.98, 129.44, 129.81, 129.94, 133.31,135.36, 135.89, 137.68, 153.50, 167.99, 168.87, 170.87, 170.98, 172.73,172.83. LC/MS (M+1)⁺=553; Anal Calcd for C₃₂H₃₂N₄O₅+0.6H₂O: C, 68.22; H,5.94; N, 9.94; Found: C, 67.95; H, 5.68; N, 9.84.

5.2353-{4-[4-(4-BENZYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To a stirred solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.44 g, 0.993 mmol) in acetonitrile (10 ml) at room temperature wasadded 4-benzylpiperidine (0.230 ml, 1.290 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.328 ml, 1.985 mmol). The mixturebecame cloudy in a couple of minutes. It was stirred at room temperatureovernight. Solvent was evaporated to give a white solid, which wasstirred in water (30 ml) and methylene chloride (50 ml). The org phasewas washed with saturated sodium bicarbonate (2×20 ml), brine (20 ml),dried and concentrated to a light yellow solid (0.5 g). The solid wasstirred in acetonitrile (8 ml) at 55° C. for one hour then filtered togive3-{4-[4-(4-Benzyl-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas an off-white solid (0.245 g, 46% yield); mp, 169-171° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 5.15min (94.1%). ¹H NMR (DMSO-d₆) δ 1.08-1.29 (m, 2H, CH₂), 1.38-1.62 (m,3H, CH₂, CH), 1.77-1.91 (m, 2H, CH₂), 1.92-2.05 (m, 1H, CHH), 2.35-2.48(m, 2H, CHH, CH), 2.57 (dd, J=1.3, 11.7 Hz, 1H, CHH), 2.69-2.81 (m, 2H,CH₂), 2.83-3.01 (m, 1H, CHH), 3.41 (s, 2H, CH₂), 4.19-4.49 (m, 2H, CH₂),5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.21 (s, 2H, CH₂), 7.10-7.20 (m, 3H,Ar), 7.21-7.37 (m, 7H, Ar), 7.38-7.53 (m, 3H, Ar), 10.97 (s, 1H, NH).¹³C NMR (DMSO-d₆) δ 22.36, 31.21, 31.72, 37.32, 42.36, 45.09, 51.56,53.18, 62.09, 69.45, 114.97, 115.21, 125.68, 127.62, 128.07, 128.73,128.93, 129.81, 129.94, 133.31, 135.03, 138.66, 140.32, 153.51, 168.01,170.98, 172.83. LC/MS (M+1)⁺=538; Anal Calcd for C₃₃H₃₅N₃O₄: C, 73.72;H, 6.56; N, 7.82; Found: C, 72.17; H, 6.08; N, 7.53.

5.2363-{4-[4-(4-ETHANESULFONYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: 4-Ethanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester

To the stirred solution of tert-butyl piperazine-1-carboxylate (1.0 g,5.37 mmol) in DCM anhydrous (10 mL) at room temperature was addedethanesulfonyl chloride (0.56 ml, 5.91 mmol) and TEA (0.898 ml, 6.44mmol). The resulting mixture was stirred at room temperature for 22.5hrs before it was diluted by DCM (40 mL). The mixture was washed withwater (20 mL) and brine (20 mL). The organic layer was concentratedunder vacuo to give 4-ethane sulfonyl-piperazine-1-carboxylic acidtert-butyl ester as a light yellow oil (1.7 g, 114% crude yield). LCMSMH (without boc)=179.

Step 2: 1-(Ethylsulfonyl)piperazine hydrochloride

To the stirred solution of tert-butyl4-(ethylsulfonyl)piperazine-1-carboxylate (1.7 g, 6.11 mmol) in DCM (5mL) was added HCl (2M in diethyl ether, 30 ml, 60.0 mmol). The reactionmixture was stirred at room temperature for 22.5 hrs and filtered. Thewhite solid was washed with diethyl ether (2×15 mL) and dried undersuction to give 1-(ethylsulfonyl) piperazine hydrochloride as a whitesolid (1.03 g, 79% yield). The product was put to next step withoutfurther purification. HNMR spectra data ¹H NMR (DMSO-d₆) δ 1.21 (t,J=7.4 Hz, 3H, CH₃), 3.04-3.25 (m, 6H, CH₂, CH₂, CH₂), 3.33-3.54 (m, 4H,CH₂, CH₂), 9.50 (br. s., 2H, NHHCl); LCMS MH=179

Step 3:3-{4-[4-(4-Ethanesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred suspension of 1-(ethylsulfonyl)piperazine hydrochloride(203 mg, 0.947 mmol) in Acetonitrile (10 mL) was added DIPEA (0.414 ml,2.369 mmol) followed by the addition of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.790 mmol). The resulting clear solution was stirred at roomtemperature for further reaction. The reaction mixture was stirred atroom temperature for 16 hrs before it was diluted by EtOAc (70 mL) andNaHCO₃ (sat., aq., 20 mL). Some solid was formed in the mixture. Themixture was filtered and the filtrate was extracted. Organic layer wasdried by MgSO₄ and filtered. The filtrate combined with the solid wasconcentrated and the residue was purified by ISCO chromatography to give3-{4-[4-(4-Ethanesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (240 mg, 56% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80, (CH₃CN/0.1% H₃PO₄), 3.82 min(99.9%); mp: 135-137° C.; ¹H NMR (DMSO-d₆) δ 1.20 (t, J=7.4 Hz, 3H,CH₃), 1.90-2.06 (m, 1H, CHH), 2.32-2.48 (m, 5H, CHH, CH₂, CH₂), 2.60(br. s., 1H, CHH), 2.82-2.99 (m, 1H, CHH), 3.04 (q, J=7.4 Hz, 2H, CH₂),3.11-3.21 (m, 4H, CH₂, CH₂), 3.52 (s, 2H, CH₂), 4.25 (d, J=17.4 Hz, 1H,CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH),5.23 (s, 2H, CH₂), 7.26-7.38 (m, 4H, Ar), 7.40-7.55 (m, 3H, Ar), 10.97(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 7.40, 22.34, 31.16, 42.16, 45.06,45.22, 51.55, 52.07, 61.23, 69.35, 114.96, 115.22, 127.66, 128.92,129.80, 129.93, 133.30, 135.37, 137.64, 153.48, 167.97, 170.96, 172.81;LCMS MH=541; Anal. Calcd for C₂₇H₃₂N₄O₆S: C, 59.98; H, 5.97; N, 10.36;Found: C, 59.67; H, 5.93; N, 10.21.

5.2373-(1-OXO-4-{4-[4-(PROPANE-2-SULFONYL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: 4-(Propane-2-sulfonyl)-piperazine-1-carboxylic acid tert-butylester

To the stirred solution of tert-butyl piperazine-1-carboxylate (1.0 g,5.4 mmol) in DCM anhydrous (10 mL) at room temperature was addedpropane-2-sulfonyl chloride (0.7 ml, 5.9 mmol) and TEA (0.89 ml, 6.44mmol). The resulting mixture was stirred at room temperature for 16 hrsbefore it was diluted by DCM (40 mL), which was washed with water (20mL) and brine (20 mL). The organic layer was concentrated under vacuo togive 4-(Propane-2-sulfonyl)-piperazine-1-carboxylic acid tert-butylester as a light brown solid (1.63 g, 104% crude yield). The crudeproduct was put to next step without further purification; LCMS MH=293.

Step 2: 1-(Isopropylsulfonyl)piperazine hydrochloride

To the stirred solution of tert-butyl4-(isopropylsulfonyl)piperazine-1-carboxylate (1.63 g, 5.6-mmol) in DCM(5 mL) was added HCl (2M in diethyl ether, 30 ml, 60.0 mmol). Theresulting reaction mixture was stirred at room temperature for 21 hrsbefore it was filtered. The white solid was washed with diethyl ether(2×15 mL) and dried under suction to give1-(isopropylsulfonyl)piperazine hydrochloride as a white solid (0.84 g,66% crude yield). The product was put to next step without furtherpurification; 1H NMR (DMSO-d₆) δ 1.23 (d, J=6.8 Hz, 6H, CH₃, CH₃),2.99-3.21 (m, 4H, CH₂, CH₂), 3.28-3.57 (m, 5H, CH, CH₂, CH₂), 9.35-9.66(m, 2H, NHHCl); LCMS MH=179.

Step 3:3-(1-Oxo-4-{4-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione

To the stirred suspension of 1-(isopropylsulfonyl)piperazinehydrochloride (217 mg, 0.9 mmol) in Acetonitrile (10 mL) was added DIPEA(0.4 ml, 2.4 mmol) followed by the addition of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.8 mmol). The resulting clear solution was stirred at roomtemperature for 17 hrs before it was added by EtOAc (70 mL) and NaHCO₃(sat., aq., 20 mL). Some solid was formed in the mixture. The mixturewas filtered and the filtrate was extracted. Organic layer was dried byMgSO₄ and filtered. The filtrate combined with the solid wasconcentrated and the residue was purified by ISCO to give3-(1-Oxo-4-{4-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (249 mg, 57% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 20/80, (CH₃CN/0.1% H₃PO₄), 5.03 min(99.2%); mp: 233-235° C.; ¹H NMR (DMSO-d₆) δ 1.21 (d, J=6.8 Hz, 6H, CH₃,CH₃), 1.91-2.06 (m, 1H, CHH), 2.34-2.48 (m, 5H, CHH, CH₂, CH₂), 2.54(br. s., 1H, CHH), 2.82-3.00 (m, 1H, CHH), 3.17-3.28 (m, 4H, CH₂, CH₂),3.28-3.37 (m, 1H, CH), 3.52 (s, 2H, CH₂), 4.25 (d, J=17.6 Hz, 1H, CHH),4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.23(s, 2H, CH₂), 7.33 (d, J=7.6 Hz, 4H, Ar), 7.39-7.54 (m, 3H, Ar), 10.97(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 16.41, 22.34, 31.16, 45.06, 45.60,51.55, 51.62, 52.52, 61.33, 69.35, 114.94, 115.22, 127.64, 128.94,129.80, 129.93, 133.28, 135.37, 137.60, 153.48, 167.97, 170.96, 172.81;LCMS MH=555; Anal. Calcd for C₂₈H₃₄N₄O₆S: C, 60.63; H, 6.18; N, 10.10;Found: C, 60.41; H, 6.03; N, 9.94.

5.2383-(4-{4-[4-(1-HYDROXY-1-METHYL-ETHYL)-PIPERIDIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the CH₃CN solution of the mixture3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.50 g, 1.12 mmol) was added DIPEA (0.394 ml, 2.256 mmol) followed by2-(piperidin-4-yl)propan-2-ol (0.194 g, 1.354 mmol) at room temperature.The mixture was stirred at room temperature overnight. The reactionmixture was concentrated then extracted using water (20 mL) and DCM (20mL). The organic layer was concentrated and the resulted solidrecrystallized from 2 mL of CH₃CN to give3-(4-{4-[4-(1-Hydroxy-1-methyl-ethyl)-piperidin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione(240 mg, 42%). m.p.: 160-162° C. LC_MS m/e=506. HPLC Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient 5/95 to 5/95CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stay at 95/5 for 5 min: 4.78min (95.2%). ¹H NMR (DMSO-d₆) δ 0.94-1.06 (m, 6H, CH₃, CH₃), 1.07-1.33(m, 3H, CH, CH₂), 1.62 (d, J=10.8 Hz, 2H, CH₂), 1.82 (t, J=10.9 Hz, 2H,CH₂), 1.91-2.07 (m, 1H, CHH), 2.35-2.47 (m, 1H, CHH), 2.57 (d, J=18.3Hz, 1H, CHH), 2.84 (d, J=11.7 Hz, 2H, CH₂), 2.89-2.99 (m, 1H, CHH), 3.42(s, 2H, CH₂), 4.02 (s, 1H, OH), 4.18-4.47 (m, 2H, CH₂), 5.11 (dd, J=5.0,13.1 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.23-7.38 (m, 4H, Ar), 7.39-7.58(m, 3H, Ar), 10.96 (s, 1H, Ar)¹³C NMR (DMSO-d₆) δ 22.33, 26.54, 26.86,31.18, 45.07, 46.94, 51.55, 53.82, 62.10, 69.44, 70.19, 114.96, 115.19,127.58, 128.75, 129.78, 129.93, 133.28, 135.00, 138.71, 153.51, 167.99,170.96, 172.81; Anal Calcd for C₂₉H₃₅N₃O₅+0.2H₂O C %: 68.40; H %: 7.01;N %: 8.25; Found: C %: 68.20; H %: 7.05; N %: 8.12.

5.2393-{1-OXO-4-[4-(3,4,5,6-TETRAHYDRO-2H-[4,4′]BIPYRIDINYL-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN solution of mixture of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.36 g, 0.82 mmol) was added N-ethyl-N-isopropylpropan-2-amine (0.284ml, 1.624 mmol) and 4-(piperidin-4-yl)pyridine (0.158 g, 0.975 mmol).The mixture was stirred at room temperature for overnight thenconcentrated on rota-vap. The resulted solid was added water 30 mL andstirred at room temperature for 2 hours. The suspension was filteredthen was recrystallized from CH3CN (3 mL) to give3-{1-Oxo-4-[4-(3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid. m.p.: 198-200° C. LC-MS m/e=525. HPLC Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient 5/95 to 5/95CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stay at 95/5 for 5 min: 4.36min (96%). ¹H NMR (DMSO-d₆) δ 1.48-1.86 (m, 4H, CH₂, CH₂), 1.90-2.17 (m,3H, CH₂, CHH), 2.32-2.44 (m, OH, CHH), 2.51-2.65 (m, 2H, CHH, CH),2.80-3.08 (m, 3H, CHH, CH₂), 3.41-3.63 (m, 2H, CH₂), 4.15-4.57 (m, 2H,CH₂), 5.11 (dd, J=5.0, 13.1 Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 7.12-7.70(m, 9H, Ar), 8.45 (dd, J=1.5, 4.5 Hz, 2H, Ar), 10.97 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 22.36, 31.20, 31.98, 40.86, 45.09, 51.58, 53.21, 69.42,114.98, 115.23, 122.31, 127.65, 129.01, 129.82, 129.95, 133.32, 135.25,149.56, 153.51, 168.01, 170.98, 172.83; Anal Calcd for C₃₁H₃₂N₄O₄+0.3H₂OC %: 70.25; H %: 6.20; N %: 10.57. Found C %: 70.05; H %: 5.92; N %:10.25.

5.2403-{4-[4-(4-BENZENESULFONYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: 4-Benzenesulfonyl-piperazine-1-carboxylic acid tert-butyl ester

To the stirred solution of tert-butyl piperazine-1-carboxylate (1.0 g,5.4 mmol) in DCM anhydrous (10 mL) at room temperature was addedbenzenesulfonyl chloride (0.75 ml, 5.9 mmol) and TEA (0.90 ml, 6.4mmol). The resulting mixture was stirred at room temperature for 18 hrsbefore it was diluted by EtOAc (40 mL) and NaHCO₃ (aq, sat, 15 mL). Themixture was extracted and organic layer was washed with brine (20 mL)and dried by MgSO₄. The organic layer was concentrated under vacuo togive 4-Benzenesulfonyl-piperazine-1-carboxylic acid tert-butyl ester asa white solid (2.0 g, 114% crude yield). It was used in the next stepwithout further purification; LCMS MH (226, loss of BOC group duringLCMS).

Step 2: 1-(Phenylsulfonyl)piperazine hydrochloride

To the stirred solution of tert-butyl4-(phenylsulfonyl)piperazine-1-carboxylate (crude) (1.75 g, 5.4 mmol) inDCM (4.5 mL) was added HCl (2M in diethyl ether) (20 ml, 40.0 mmol). Theresulting mixture was stirred at room temperature for 3 days before itwas filtered and the white solid was washed with Ether (2×30 mL) anddried under suction to give 1-(phenylsulfonyl)piperazine hydrochlorideas a white solid (1.4 g, 100% crude yield). The compound was used in thenext step without further purification. ¹H NMR (DMSO-d₆) δ 3.16 (s, 8H,CH₂, CH₂, CH₂, CH₂), 7.61-7.84 (m, 5H, Ar), 9.42 (br. s., 2H, NHHCl);LCMS MH=227.

Step 3:3-{4-[4-(4-Benzenesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred suspension of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (360 mg, 0.8 mmol) in Acetonitrile (10 mL) wasadded DIPEA (0.43 ml, 2.4 mmol) and 1-(phenylsulfonyl)piperazinehydrochloride (256 mg, 0.98 mmol) at room temperature. The resultingmixture was stirred at room temperature for 21 hrs before it was addedby EtOAc (50 mL) and NaHCO₃ (sat., aq., 20 mL). The mixture wasextracted and organic layer was dired by MgSO₄. Organic layer wasconcentrated and the residue was purified by ISCO. The solid product wasfurther purified by being stirred in DCM (5 mL) and diethyl ether (30mL) to give3-{4-[4-(4-Benzenesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (392 mg, 82% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75, (CH₃CN/0.1% H₃PO₄), 3.79 min(99.0%); mp: 220-222° C.; ¹H NMR (DMSO-d₆) δ 1.90-2.04 (m, 1H, CHH),2.33-2.47 (m, 5H, CHH, CH₂, CH₂), 2.54-2.63 (m, 1H, CHH), 2.80-2.94 (m,5H, CH₂, CH₂, CHH), 3.46 (s, 2H, CH₂), 4.23 (d, J=17.6 Hz, 1H, CHH),4.40 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.3 Hz, 1H, CHH), 5.20(s, 2H, CH₂), 7.14-7.54 (m, 7H, Ar), 7.56-7.86 (m, 5H, Ar), 10.97 (s,1H, NH); ¹³C NMR (DMSO-d₆) 22.33, 31.16, 45.04, 45.92, 51.37, 51.53,60.98, 69.32, 114.93, 115.20, 127.51, 127.63, 128.78, 129.36, 129.78,129.90, 133.23, 133.28, 134.68, 135.33, 137.53, 153.45, 167.97, 170.95,172.81; LCMS MH=589; Anal. Calcd for C₃₁H₃₂N₄O₆S+.4H₂O: C, 62.49; H,5.55; N, 9.40; Found: C, 62.59; H, 5.40; N, 9.33.

5.2413-{4-[4-(4-HYDROXY-4-PHENYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN solution (10 mL)3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.28 g, 0.62 mmol) was added N-ethyl-N-isopropylpropan-2-amine (0.22ml, 1.24 mmol) followed by 4-phenylpiperidin-4-ol (0.13 g, 0.76 mmol).The mixture was stirred at room temperature overnight. The reactionmixture was concentrated on rota-vap and the resulted solid wasextracted using CH₂Cl₂ and Water. The organic layer was concentrated togive a solid which was recrystallized from CH3CN (3 mL) to give3-{4-[4-(4-Hydroxy-4-phenyl-piperidin-1-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (154 mg, 44%). Melting point: 140-142° C. LC-MSm/e=540. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240nm, gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stayat 95/5 for 5 min: 5.02 min (95%). ¹H NMR (DMSO-d₆) δ 1.58 (d, J=13.0Hz, 2H, CH₂), 1.80-2.10 (m, 3H, CH₂, CHH), 2.32-2.43 (m, 3H, CHH, CH₂),2.60 (br. s., 3H, CHH, CH₂), 2.79-3.06 (m, 1H, CHH), 3.57 (br. s., 2H,CH₂), 4.04-4.56 (m, 2H, CHH), 4.80 (br. s., 1H, OH), 5.11 (d, J=8.1 Hz,1H, NCH), 5.24 (s, 2H, CH₂), 7.06-7.66 (m, 12H, Ar), 10.97 (s, 1H, NH).¹³C NMR (DMSO-d₆) δ 22.33, 31.18, 31.25, 45.06, 48.89, 51.55, 69.41,114.94, 115.20, 124.71, 126.13, 127.63, 127.77, 129.80, 129.93, 133.28,153.49, 161.07, 167.99, 170.96, 172.81. Anal Calcd for C₃₂H₃₃N₃O₅+0.6H₂OC %: 69.64; H %: 5.70; N %: 7.27. Found C %: 69.83; H %: 6.26; N %:7.63.

5.2422-(2,6-DIOXOPIPERIDIN-3-YL)-4-((4-((4-ISOPROPYLPIPERIDIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLINE-1,3-DIONE

4-(4-(Bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(250 mg, 0.547 mmol) was slurried in dry MeCN (10 mL). To the slurry,was added 4-isopropylpiperidine (139 mg, 1.093 mmol) and the mixture wasstirred at room temperature resulting in a clear solution within severalminutes. After ˜1 h, a thick precipitate was formed. The volatiles wereremoved in vacuo and the residue was partitioned between aq 1N NaHCO₃(40 mL) and EtOAc (˜100 mL). The aqueous layer was saturated with solidNa₂CO₃ and then extracted once more with EtOAc (˜50 mL). The combinedorganic layer was washed with brine, dried (Na₂SO₄), and concentrated invacuo to give a yellowish solid. The solid was triturated with water,filtered, and then washed with additional water (˜200 mL, total). Theremaining solid was washed with hexanes (˜1500 L, total), suction dried,and then dried further in a vacuum oven at 60° C. to give2-(2,6-dioxopiperidin-3-yl)-4-((4-((4-isopropylpiperidin-1-yl)methyl)benzyl)-oxy)isoindoline-1,3-dioneas a pale yellow solid (220 mg, 80%): HPLC: Waters Symmetry C₁s, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 6.86 min (96.4%).mp: 220-222° C.; ¹H NMR (DMSO-d₆) δ 0.82 (s, 3H, CH₃), 0.85 (s, 3H,CH₃), 0.89-1.06 (m, 1H, CHH), 1.08-1.26 (m, 2H, CHH, CHH, CHH),1.31-1.46 (m, 1H, CHH), 1.48-1.66 (m, 2H, CH₂), 1.85 (t, J=10.7 Hz, 2H,CH₂), 1.95-2.13 (m, 1H, CHH), 2.52-2.66 (m, 2H, CHH, CHH), 2.72-3.00 (m,3H, CHH, CHH, CHH), 3.42 (s, 2H, CH₂), 5.09 (dd, J=5.5, 12.8 Hz, 1H,CH), 5.35 (s, 2H, CH₂), 7.25-7.38 (m, 2H, Ar), 7.40-7.52 (m, 3H, Ar),7.60 (d, J=8.5 Hz, 1H, Ar), 7.74-7.92 (m, 1H, Ar), 11.09 (br. s., 1H,NH); ¹³C NMR (DMSO-d₆) δ 19.64, 21.93, 28.86, 30.90, 31.92, 41.84,48.73, 53.65, 62.15, 69.98, 115.48, 116.56, 120.21, 127.20, 128.78,133.26, 134.52, 136.97, 138.65, 155.53, 165.29, 166.75, 169.87, 172.71;LCMS: MH=504; Anal Calcd for C₂₉H₃₃N₃O₅+0.16H₂O; C, 68.77; H, 6.63; N,8.30; Found: C, 68.77; H, 6.88; N, 8.22.

5.2433-{4-[4-(1-BENZYL-PIPERIDIN-4-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: Preparation of4-{4-[2-(1-Carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperidine-1-carboxylicacid tert-butyl ester

Triphenyl phosphene (polymer-supported, 1.6 mmol/g, 3.3 g) was added toa stirred white suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (2.444 g,8.36 mmol) in THF (100 ml) at 0° C. After ten minutes, diisopropyldiazene-1,2-dicarboxylate (2.470 ml, 12.54 mmol) was added and stirredfor 40 minutes and then tert-butyl4-(4-(hydroxymethyl)benzyl)piperidine-1-carboxylate (3.32 g, 10.87 mmol)in THF (20 ml) was added. The mixture was stirred at 0° C. and warmed upto room temperature overnight. The suspension was filtered, rinsed withMeOH (2×20 ml), CH₂Cl₂ (2×30 ml), and the filtrate was evaporated togive an oil, which was dissolved in CH₂C₂ (80 ml), washed with SatNaHCO₃ (50 ml), concentrated and then purified by silica gel column togive4-{4-[2-(1-Carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperidine-1-carboxylicacid tert-butyl ester as a foamy oil (2.2 g, 45% yield). It was used inthe next step without further purification.

Step 2: Preparation of4-Carbamoyl-4-[1-oxo-4-(4-piperidin-4-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

To a stirred solution of tert-butyl4-(4-((2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)piperidine-1-carboxylate(2.2 g, 3.80 mmol) in CH₂Cl₂ (10 ml) at room temperature was addedhydrogen chloride (2 M in ether) (10 ml, 38.0 mmol). After four hours,the suspension was filtered, rinsed with ether and the resulting yellowsolid was dried to give 2.02 g, 111% crude yield (HCl salt). The productwas used later in the next step without further purification.

Step 3: Preparation of4-{4-[4-(1-Benzyl-piperidin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-4-carbamoyl-butyricacid methyl ester

To a stirred mixture of methyl5-amino-5-oxo-4-(1-oxo-4-(4-(piperidin-4-ylmethyl)benzyloxy)isoindolin-2-yl)pentanoatehydrochloride (0.321 g, 0.622 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.411 ml, 2.488 mmol) in acetonitrile(10 ml) was added (bromomethyl)benzene (0.074 ml, 0.622 mmol). After 15minutes, the solvent was evaporated to give an oil, which was stirred inwater (20 ml), sat NaHCO3 (10 ml), and ethyl acetate (30 ml). The orgphase was dried and evaporated to give an oil (0.33 g, 93% yield). Itwas used in the next step without further purification.

Step 4: Preparation of3-{4-[4-(1-Benzyl-piperidin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To a stirred solution of methyl5-amino-4-(4-(4-((1-benzylpiperidin-4-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.33 g, 0.579 mmol) in THF (8 ml) in an ice-water bath was addedpotassium 2-methylpropan-2-olate (0.065 g, 0.579 mmol). After tenminutes, the mixture was quenched with 1 N HCl (to pH=1-2), neutralizedwith Sat NaHCO₃ (to pH=7-8), and stirred in water (10 ml) and CH₂Cl₂ (30ml). The organic phase was washed with water (20 ml), brine (20 ml),dried over Na₂SO₄ and concentrated to an oil, which was purified onsilica gel column to give3-{4-[4-(l-Benzyl-piperidin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas an off-white solid (121 mg, 39% yield); mp, 110-112° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 27/73 in10 min (CH₃CN/0.1% H₃PO₄): 5.48 min (96.8%). ¹H NMR (DMSO-d₆) δ1.10-1.30 (m, 2H, CH₂), 1.39-1.60 (m, 3H, CH₂, CHH), 1.84 (t, J=11.4 Hz,2H, CH₂), 1.92-2:03 (m, 1H, CHH), 2.35-2.47 (m, 1H, CHH), 2.57 (d,J=10.8 Hz, 1H, CHH), 2.69-2.81 (m, 2H, CH₂), 2.82-3.00 (m, 1H, CHH),3.40 (s, 2H, CH₂), 4.18-4.46 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H,NCH), 5.19 (s, 2H, CH₂), 7.13-7.35 (m, 9H, Ar), 7.38 (d, J=8.1 Hz, 2H,Ar), 7.44-7.52 (m, 1H, Ar), 10.96 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ22.36, 31.20, 31.72, 37.30, 42.04, 45.09, 51.56, 53.17, 62.39, 69.49,114.95, 115.19, 126.72, 127.68, 128.06, 128.61, 129.06, 129.81, 129.94,133.29, 133.95, 138.72, 140.26, 153.54, 168.01, 170.96, 172.82. LC/MSm/e=538. Anal Calcd for C₃₃H₃₅N₃O₄ (+0.6H₂O): C, 72.27; H, 6.65; N,7.66. Found: C, 72.10; H, 6.38; N, 7.49.

5.2442-(2,6-DIOXOPIPERIDIN-3-YL)-4-((4-((4-PHENYLPIPERIDIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLINE-1,3-DIONE

To a mixture of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(250 mg, 0.547 mmol) and 4-phenylpiperidine (93 mg, 0.574 mmol) in dryMeCN (10 mL), was added DIEA (0.143 mL, 0.820 mmol) and the resultingsuspension was stirred at room temperature. After ˜20 h more4-phenylpiperidine (10 mg, 0.06 mmol) was added and stirring wascontinued for 1 day. To push reaction to completion, more DIEA (100 μL)was added and the mixture was stirred at room temperature overnight. Thecrude reaction mixture was treated with additional DIEA (0.143 mL) andthen warmed to 80° C. for ˜1 h. The mixture was allowed to cool slowlywith gentle stirring. After 2 h, the slurry was filtered on a mediumfritted funnel with suction. Residual solid the reaction vial was rinsedonto funnel with minimal MeCN (˜1 mL). The solid cake on the funnel waswashed with water (3×10 mL). The remaining solid was suction dried, thenfurther dried in vacuum oven at 60° C. for 4 h to give2-(2,6-dioxopiperidin-3-yl)-4-((4-((4-phenylpiperidin-1-yl)methyl)benzyl)-oxy)isoindoline-1,3-dioneas a white solid (254 mg, 86%): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 ml/min, 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 3.34 min (99.6%); mp:142-144° C.; ¹H NMR (DMSO-d₆) δ 1.52-1.83 (m, 4H, CHH, CHH, CHH, CHH),1.93-2.17 (m, 3H, CHH, CHH, CHH), 2.39-2.68 (m, 3H, CHH, CHH, CHH),2.77-3.02 (m, 3H, CHH, CHH, CHH), 3.51 (s, 2H, CH₂N), 5.09 (dd, J=5.4,12.7 Hz, 1H, CH), 5.36 (s, 2H, CH₂), 7.08-7.33 (m, 5H, Ar), 7.33-7.42(m, 2H, Ar), 7.47 (d, J=7.9 Hz, 3H, Ar), 7.61 (d, J=8.5 Hz, 1H, Ar),7.83 (dd, J=7.4, 8.5 Hz, 1H, Ar), 11.11 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ21.95, 30.90, 33.06, 41.81, 48.73, 53.60, 62.10, 69.98, 115.48, 116.56,120.21, 125.92, 126.66, 127.23, 128.25, 128.92, 133.26, 134.63, 136.99,138.45, 146.23, 155.55, 165.29, 166.75, 169.87, 172.72; LCMS: MH=538;Anal Calcd for C₃₂H₃₁N₃O₅+0.5H₂O: C, 70.31; H, 5.90; N, 7.69; Found: C,70.39; H, 5.71; N, 7.65.

5.2452-(2,6-DIOXOPIPERIDIN-3-YL)-4-((4-((4-(METHYLSULFONYL)PIPERIDIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLINE-1,3-DIONE

To a mixture of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(250 mg, 0.547 mmol) and 4-(methylsulfonyl)piperidine (98 mg, 0.601mmol) in MeCN (10 mL, 191 mmol) was added DIEA (0.143 mL, 0.820 mmol)and the resulting mixture (white suspension) was stirred at roomtemperature. To the reaction mixture was added DIEA (0.143 mL, 0.820mmol) and the slurry was heated to 80° C. and kept at that temperaturefor ˜1 h, then allowed to cool to room temperature slowly with gentlestirring. After 2 h, the slurry was filtered. The solid cake on thefunnel was washed with water (3×10 mL). The remaining solid was suctiondried, then further dried in vacuum oven at 60° C. for 4 h. to give2-(2,6-Dioxopiperidin-3-yl)-4-((4-((4-(methylsulfonyl)piperidin-1-yl)methyl)benzyl)oxy)isoindoline-1,3-dioneas a white solid (270 mg, 92% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 18/82 CH₃CN/0.1% H₃PO₄, 4.85 min (98.9%);mp: 204-206° C. ¹H NMR (DMSO-d₆) δ 1.60 (qd, J=4.0, 12.6 Hz, 2H, CHH,CHH), 1.88-2.12 (m, 4H, CHH, CHH, CHH, CHH), 2.41-2.66 (m, 3H, CHH, CHH,CHH), 2.81-2.97 (m, 6H, CH₃, CHH, CHH, CHH), 2.98-3.13 (m, 1H, CH), 3.49(s, 2H, CH₂), 5.09 (dd, J=5.4, 12.7 Hz, 1H, CH), 5.35 (s, 2H, CH₂), 7.34(d, J=8.1 Hz, 2H, Ar), 7.47 (dd, J=2.0, 7.6 Hz, 3H, Ar), 7.60 (d, J=8.5Hz, 1H, Ar), 7.83 (dd, J=7.4, 8.3 Hz, 1H, Ar), 11.11 (s, 1H, NH). ¹³CNMR (DMSO-d₆) δ 21.95, 24.43, 30.90, 37.30, 48.73, 51.43, 58.73, 61.36,69.95, 115.50, 116.56, 120.19, 127.29, 128.82, 133.26, 134.76, 136.97,138.07, 155.53, 165.29, 166.75, 169.87, 172.72; LCMS: MH=540; Anal Calcdfor C₂₇H₂₉N₃O₇S+0.6H₂O+0.3 MeCN: C, 58.91; H, 5.57; N, 8.21; S, 5.70;Found: C, 58.93; H, 5.41; N, 8.11; S, 5.61.

5.2463-{4-[4-(1-CYCLOPROPYLMETHYL-PIPERIDIN-4-YLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: Preparation of4-{4-[2-(1-Carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperidine-1-carboxylicacid tert-butyl ester

Triphenyl phosphene (polymer-supported, 1.6 mmol/g, 3.3 g) was added toa stirred white suspension of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (2.444 g,8.36 mmol) in THF (100 ml) at 0° C. After ten minutes, diisopropyldiazene-1,2-dicarboxylate (2.470 ml, 12.54 mmol) was added and stirredfor 40 minutes and then tert-butyl4-(4-(hydroxymethyl)benzyl)piperidine-1-carboxylate (3.32 g, 10.87 mmol)in THF (20 ml) was added. The mixture was stirred at 0° C. and warmed upto room temperature overnight. The suspension was filtered, rinsed withMeOH (2×20 ml), CH₂Cl₂ (2×30 ml), and the filtrate was evaporated togive an oil, which was dissolved in CH₂Cl₂ (80 ml), washed with SatNaHCO₃ (50 ml), concentrated and then purified by silica gel column togive4-{4-[2-(1-Carbamoyl-3-methoxycarbonyl-propyl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-benzyl}-piperidine-1-carboxylicacid tert-butyl ester as a foamy oil (2.2 g, 45% yield). It was used inthe next step without further purification.

Step 2: Preparation of4-Carbamoyl-4-[1-oxo-4-(4-piperidin-4-ylmethyl-benzyloxy)-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

To a stirred solution of tert-butyl4-(4-((2-(1-amino-5-methoxy-1,5-dioxopentan-2-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)piperidine-1-carboxylate(2.2 g, 3.80 mmol) in CH₂Cl₂ (10 ml) at room temperature was addedhydrogen chloride (2 M in ether) (10 ml, 38.0 mmol). After four hours,the suspension was filtered, rinsed with ether and the resulting yellowsolid was dried to give 2.02 g, 111% crude yield (HCl salt). The productwas used later in the next step without further purification.

Step 3: Preparation of4-Carbamoyl-4-{4-[4-(-cyclopropylmethyl-piperidin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester

To a stirred mixture of methyl5-amino-5-oxo-4-(1-oxo-4-(4-(piperidin-4-ylmethyl)benzyloxy)isoindolin-2-yl)pentanoatehydrochloride (0.325 g, 0.630 mmol)) andN-ethyl-N-isopropylpropan-2-amine (0.416 ml, 2.52 mmol) in acetonitrile(10 ml) was added (bromomethyl)cyclopropane (0.061 ml, 0.630 mmol)). Themixture was heated at 55° C. for 5 hours and then at room temperatureovernight. The solvent was evaporated to give an oil, which was stirredin water (20 ml), sat NaHCO₃ (10 ml), and ethyl acetate (40 ml). Theorganic phase was washed with water (20 ml), brine (20 ml), dried andevaporated to give4-Carbamoyl-4-{4-[4-(1-cyclopropylmethyl-piperidin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-butyricacid methyl ester as an oil (0.28 g, 83% yield). It was used in the nextstep without further purification.

Step 4: Preparation of3-{4-[4-(1-Cyclopropylmethyl-piperidin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To a stirred solution of methyl5-amino-4-(4-(4-((1-(cyclopropylmethyl)piperidin-4-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.28 g, 0.525 mmol) in THF (10 ml) in an ice-water bath was addedpotassium 2-methylpropan-2-olate (0.059 g, 0.525 mmol) and stirred for10 minutes. To the mixture was added 1 N HCl (to pH=1) then neutralizedwith Sat NaHCO₃ (to pH=7). Water (10 ml) and CH₂Cl₂ (20 ml) was addedand the mixture was washed with water (15 ml), brine (10 ml), dried overNa₂SO₄ and concentrated to a brown oil, which was purified by silica gelcolumn to give3-{4-[4-(1-Cyclopropylmethyl-piperidin-4-ylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a foamy solid (20 mg, 8% yield); mp, N/A. HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90 to 95/5 in 5min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 4.62 min (98.7%).HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm,isocratic at 27/73 in 10 min (CH₃CN/0.1% H₃PO₄): 4.58 min (95.4%). ¹HNMR (DMSO-d₆) δ 0.05-0.14 (m, 2H, CH₂), 0.44-0.57 (m, 2H, CH₂),0.78-0.96 (m, 1H, CH), 1.28-1.46 (m, 2H, CH₂), 1.47-1.58 (m, 1H, CH),1.59-1.72 (m, 2H, CH₂), 1.86-2.01 (m, 2H, CH₂), 2.12-2.43 (m, 4H,CH₂CH₂), 2.57 (d, J=6.6 Hz, 2H, CH₂), 2.73-2.96 (m, 2H, CH₂), 3.09 (dt,J=3.1, 11.8 Hz, 2H, CH₂), 4.21-4.55 (m, 2H, CH₂), 5.10 (s, 2H, CH₂),5.21 (dd, J=5.3, 13.2 Hz, 1H, NCH), 7.06-7.21 (m, 3H, Ar), 7.31 (d,J=7.9 Hz, 2H, Ar), 7.38-7.56 (m, 2H, Ar). (The NH proton was barelyseen). ¹³C NMR (CHLOROFORM-d) δ 0.03, 4.05, 8.18, 23.49, 31.64, 31.72,37.75, 42.79, 45.15, 51.86, 53.75, 63.90, 70.30, 114.61, 116.40, 127.58,129.55, 129.90, 130.12, 133.17, 133.68, 140.88, 153.91, 169.39, 169.74,171.41. LC/MS m/e=502.

5.2473-(4-{4-[4-(4-FLUORO-PHENYL)-PIPERIDIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.513 g, 1.157 mmol) was added 4-(4-fluorophenyl)piperidinehydrochloride (0.311 g, 1.736 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.574 ml, 3.47 mmol) at roomtemperature. The cloudy mixture was stirred at room temperature startingfor two hours. Solvent CH₃CN was evaporated, and to the residue wasadded water (20 ml) and methylene chloride (40 ml). It was washed withsaturated sodium bicarbonate (2×15 ml), water (20 ml), brine (20 ml),dried over Na₂SO₄ and concentrated to an oil, which was purified bysilica gel column (MeOH/EtOAc) to give3-(4-{4-[4-(4-Fluoro-phenyl)-piperidin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneasa white solid (0.315 g, 50% yield); mp, 180-182° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 4.79min (95.7%). ¹H NMR (DMSO-d₆) δ 1.51-1.80 (m, 4H, CH₂CH₂), 1.89-2.12 (m,3H, CH, CH₂), 2.35-2.47 (m, 1H, CHH), 2.53-2.63 (m, 2H, CH, CHH),2.83-2.99 (m, 3H, CHH, CH₂), 3.50 (s, 2H, CH₂), 4.19-4.48 (m, 2H, CH₂),5.11 (dd, J=5.2, 13.3 Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 7.04-7.15 (m, 2H,Ar), 7.22-7.39 (m, 6H, Ar), 7.41-7.53 (m, 3H, Ar), 10.97 (s, 1H, NH).¹³C NMR (DMSO-d₆) δ 22.36, 31.21, 33.16, 41.02, 45.09, 51.58, 53.55,62.10, 69.45, 114.75, 115.03, 115.23, 127.62, 128.35, 128.45, 128.92,129.82, 129.95, 133.31, 135.14, 138.44, 142.35, 153.51, 159.00, 162.19,168.01, 170.98, 172.83. LC/MS m/e=542. Anal Calcd for C₃₂H₃₂N₃O₄F: C,70.96; H, 5.96; N, 7.76; F, 3.51; Found: C, 70.68; H, 5.90; N, 7.64; F,3.54.

5.2483-(4-{4-[4-(4-FLUORO-BENZYL)-PIPERIDIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.528 g, 1.191 mmol) was added 4-(4-fluorobenzyl)piperidine (0.345 g,1.787 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.394 ml, 2.382 mmol)at room temperature. The cloudy mixture was stirred at room temperaturestarting for two hours. Solvent CH₃CN was evaporated, and to the residuewas stirred in a mixture of water (20 ml), saturated sodium bicarbonate(10 ml) and methylene chloride (50 ml). The mixture was washed withwater (2×20 ml), brine (10 ml), dried over sodium sulfate andconcentrated to a white solid, which was purified by silica gel column(MeOH/CH₂Cl₂) to give3-(4-{4-[4-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white foamy solid (0.224 g, 34% yield); mp, 148-150° C. HPLC:Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from10/90 to 90/10 in 5 min, isocratic at 90/10 in 5 min (CH₃CN/0.1% H₃PO₄),4.86 min (95.8%). ¹H NMR (DMSO-d₆) δ 1.08-1.27 (m, 2H, CH₂), 1.36-1.59(m, 3H, CHH, CH₂), 1.77-1.91 (m, 2H, CH₂), 1.93-2.04 (m, 1H, CHH),2.35-2.48 (m, 2H, CHH, CHH), 2.53-2.63 (m, 1H, CHH), 2.70-2.81 (m, 2H,CH₂), 2.83-3.00 (m, 1H, CHH), 3.41 (s, 2H, CH₂), 4.18-4.47 (m, 2H, CH₂),5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.21 (s, 2H, CH₂), 7.02-7.12 (m, 2H,Ar), 7.13-7.22 (m, 2H, Ar), 7.25-7.36 (m, 4H, Ar), 7.38-7.53 (m, 3H,Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.36, 31.21, 31.60, 37.32,41.37, 45.09, 51.58, 53.15, 62.07, 69.45, 114.57, 114.85, 114.97,115.21, 127.61, 128.73, 129.81, 129.94, 130.55, 130.65, 133.31, 135.04,136.46, 138.66, 153.51, 158.98, 162.17, 168.01, 170.98, 172.83. LC/MSm/e⁺=556. Anal Calcd for C₃₃H₃₄N₃O₄F: C, 71.33; H, 6.17; N, 7.56; Found:C, 71.02; H, 5.84; N, 7.47.

5.2493-(4-{4-[4-(3-FLUORO-PHENYL)-PIPERIDIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the CH₂Cl₂ solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.5 g, 1.128 mmol) was added 4-(3-fluorophenyl)piperidine (0.101 g,0.564 mmol) and DIPEA (0.146 g, 1.13 mmol). The resulted solution wasstirred at room temperature for 2 hours. The mixture was added water (15mL) and extracted. The organic layer was concentrated and purified onsilica gel column eluted with CH₂Cl₂ and MeOH. The resulted solid wasrecrystallized from CH₃CN (5 mL) to give3-(4-{4-[4-(3-fluoro-phenyl)-piperidin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (430 mg, 70%). MeltingPoint: 200-202° C. LC-MS m/e=542. HPLC Waters Symmetry C-18, 3.9×150 mm,5 micro, 1 mL/min, 240 nm, gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂Oduring 5 min and stay at 95/5 for 5 min:6.95 min (94.75%). ¹H NMR(DMSO-d₆) δ 1.38-1.80 (m, 4H, CH₂, CH₂), 1.86-2.15 (m, 3H, CHH, CH₂),2.30-2.45 (m, J=4.2 Hz, 1H, CHH), 2.55-2.68 (m, 1H, CHH), 2.76-3.05 (m,3H, CHH, CH₂), 3.50 (s, 2H, CH₂), 4.09-4.53 (m, 2H, CH₂), 5.11 (dd,J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 6.79-7.19 (m, 3H, Ar),7.24-7.60 (m, 8H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.38,31.21, 32.80, 41.50, 45.09, 51.58, 53.46, 62.07, 69.45, 112.53, 112.81,113.30, 113.58, 114.97, 115.23, 122.84, 127.62, 128.93, 129.82, 129.95,130.06, 130.16, 133.32, 135.16, 138.41, 149.26, 149.34, 153.51, 160.69,163.89, 168.01, 170.98, 172.83. Anal Calcd for C₃₂H₃₂FN₃O₄, C, 70.96%;H, 5.96%; N, 7.76%; Found: C, 70.57%; H, 6.01%; N, 7.67%.

5.2502-(2,6-DIOXOPIPERIDIN-3-YL)-4-((4-((4-(TRIFLUOROMETHYL)PIPERIDIN-1-YL)METHYL)BENZYL)-OXY)ISOINDOLINE-1,3-DIONE

To a mixture of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(250 mg, 0.547 mmol) and 4-(trifluoromethyl)piperidine hydrochloride(114 mg, 0.601 mmol) in MeCN (10 mL), was added DIEA (0.334 mL, 1.914mmol) and the resulting suspension was stirred at room temperature for˜15 h. The reaction vial cap was removed and the mixture was heated to80° C. for ˜4.5 h. The concentrated reaction mixture (˜5 mL) waspartitioned between EtOAc (˜150 mL) and water (˜30 mL). The organiclayer was washed with 1N NaHCO₃ (2×30 mL). and brine, dried (Na₂SO₄),and concentrated in vacuo to give a solid residue. MeCN (˜3 mL) andwater ((˜25 mL) were added and the solid was sonicated at roomtemperature with agitation until a finely dispersed suspension wasobtained. The solid was collected on a medium fritted funnel and driedin a vacuum oven at 60° C. to give2-(2,6-dioxopiperidin-3-yl)-4-((4-((4-(trifluoromethyl)piperidin-1-yl)methyl)benzyl)-oxy)isoindoline-1,3-dioneas an off-white solid (243 mg, 84% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 3.53 min(99.2%); mp: 190-192° C.; ¹H NMR (DMSO-d₆) δ 1.36-1.55 (m, 2H, CHH,CHH), 1.66-1.83 (m, 2H, CHH, CHH), 1.87-2.14 (m, 3H, CHH, CHH, CHH),2.15-2.38 (m, 1H, CH), 2.40-2.68 (m, 2H, CHH, CHH), 2.77-3.00 (m, 3H,CHH, CHH, CHH), 3.48 (s, 2H, CH₂N), 5.09 (dd, J=5.5, 12.8 Hz, 1H, CH),5.35 (s, 2H, CH₂O), 7.25-7.40 (m, 2H, Ar), 7.44-7.53 (m, 3H, Ar), 7.60(d, J=8.5 Hz, 1H, Ar), 7.83 (dd, J=7.4, 8.5 Hz, 1H, Ar), 11.11 (s, 1H,NH); residual EtOAc (˜0.07 eq); ¹³C NMR (DMSO-d₆) δ 21.95, 24.19, 30.90,39.07, 48.73, 51.39, 61.61, 69.95, 115.50, 116.56, 120.19, 127.29,128.84, 133.26, 134.73, 136.99, 138.12, 155.53, 165.29, 166.75, 169.87,172.72; signal for CF3 and CCF3 is partially masked by DMSO-d₆; ¹⁹F NMR(DMSO-d₆) δ −72.35; LCMS: MH=530; Anal Calcd forC₂₇H₂₆F₃N₃O₅+0.1H₂O+0.07 EtOAc: C, 60.96; H, 5.02; N, 7.82; F, 10.60:Found: C, 61.17; H, 4.98; N, 7.46; F, 10.24.

5.2512-(2,6-DIOXOPIPERIDIN-3-YL)-4-((4-(PIPERIDIN-1-YLMETHYL)BENZYL)OXY)ISOINDOLINE-1,3-DIONE

To a suspension of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(230 mg, 0.503 mmol) and piperidine (0.055 mL, 0.553 mmol) in dry MeCN(15 mL, 287 mmol), was added DIEA (0.307 mL, 1.760 mmol) and theresulting suspension was stirred at room temperature for 2.5 h. Thereaction mixture was concentrated in vacuo to glassy solid. Triturationof the solid with a solution of ˜1:1 MeCN/Et₂O (˜10 mL) produced awell-dispersed slurry. The solid was filtered and washed with additionalEt₂O (40 mL). The remaining was partitioned between EtOAc (˜150 mL) and1 N Na₂CO₃ (˜30 mL). The organic layer was washed with additional 1 NNa₂CO₃ (˜30 mL) and brine, then dried (Na₂SO₄) and concentrated in vacuoto glassy solid. The solid was triturated with extensive sonication in asolution of MeCN (˜2 mL) and Et₂O (˜20 mL) until a finely dispersedsolid was formed. The solid was collected on a medium fritted funnelwith suction, then washed with additional Et₂O (˜20 mL). The cake wasdried in a vacuum oven overnight at 50° C. give2-(2,6-dioxopiperidin-3-yl)-4-((4-(piperidin-1-ylmethyl)benzyl)oxy)isoindoline-1,3-dioneas a tan solid (110 mg, 47%): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 ml/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 4.47 min (98.9%); mp:153-155° C.; ¹H NMR (DMSO-d₆) δ 1.38 (d, J=4.7 Hz, 2H, CH₂), 1.43-1.59(m, 4H, CH₂, CH₂), 1.94-2.13 (m, 1H, CHH), 2.19-2.40 (m, 4H, CH₂, CH₂),2.42-2.67 (m, 2H, CHH, CHH), 2.77-2.99 (m, 1H, CHH), 3.42 (s, 2H, CH₂N),5.09 (dd, J=5.4, 12.9 Hz, 1H, CH), 5.35 (s, 2H, CH₂O), 7.26-7.37 (m, 2H,Ar), 7.40-7.53 (m, 3H, Ar), 7.60 (d, J=8.5 Hz, 1H, Ar), 7.82 (dd, J=7.4,8.3 Hz, 1H, Ar), 11.11 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.95, 23.96,25.51, 30.90, 48.73, 53.85, 62.50, 69.98, 1 15.47, 116.56, 120.19,127.19, 128.82, 133.24, 134.54, 136.97, 138.52, 155.53, 165.27, 166.75,169.87, 172.71; LCMS: MH=462; Anal Calcd for C₂₆H₂₇N₃O₅+0.18H₂O: C,67.19; H, 5.93; N, 9.04; Found: C, 67.18; H, 5.78; N, 8.84.

5.2524-((4-((4,4-DIMETHYLPIPERIDIN-1-YL)METHYL)BENZYL)OXY)-2-(2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE

To a mixture of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(250 mg, 0.547 mmol) and 4,4-dimethylpiperidine hydrochloride (90 mg,0.601 mmol) in dry MeCN (10 mL), was added DIEA (0.334 mL, 1.914 mmol).The resulting suspension was stirred at room temperature for 17 h thenthe vial cap was removed and the mixture was warmed up to 75° C. After˜2.5 h, ˜½ the volume remained as a thick suspension. The mixture wascooled with gentle stirring and then aged 4° C. overnight. To themixture was added DIEA (250 μL) with stirring for 30 min. The slurry wasfiltered on a medium fritted funnel with suction and the cake was washedwith water (˜30 mL). The collected solid was suction dried and thendried further in vacuum oven at 50° C. for 6 h to give4-((4-((4,4-dimethylpiperidin-1-yl)methyl)benzyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneas an off-white solid (230 mg, 86%): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 3.88 min (97.8%);mp: 208-210° C.: ¹H NMR (DMSO-d₆) δ 0.89 (s, 6H, CH₃, CH₃), 1.19-1.41(m, 4H, CH₂, CH₂), 1.95-2.15 (m, 1H, CHH), 2.20-2.42 (m, 4H, CH₂, CH₂),2.42-2.66 (m, 2H, CHH, CHH), 2.79-2.98 (m, 1H, CHH), 3.46 (s, 2H, CH₂),5.09 (dd, J=5.5, 12.8 Hz, 1H, CH), 5.34 (s, 2H, CH₂O), 7.28-7.39 (m, 2H,Ar), 7.39-7.52 (m, 3H, Ar), 7.60 (d, J=8.5 Hz, 1H, Ar), 7.82 (dd, J=7.4,8.5 Hz, 1H, Ar), 11.11 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.95, 28.04,28.14, 30.90, 38.25, 48.73, 49.32, 62.03, 69.98, 115.48, 116.56, 120.19,127.20, 128.81, 133.24, 134.57, 136.97, 138.68, 155.53, 165.27, 166.75,169.87, 172.72; LCMS: MH=490; Anal Calcd for C₂₈H₃₁N₃O₅+0.3H₂O: C,67.94; H, 6.43; N, 8.49; Found: C, 67.91; H, 6.42; N, 8.60.

5.2533-[4-(4-BROMOMETHYL-BENZYLOXY)-1-OXO-13-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.486 g, 1.096 mmol) was added 1,4′-bipiperidine dihydrochloride (0.397g, 1.645 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.725 ml, 4.39mmol) at room temperature. The cloudy mixture was stirred at roomtemperature for two hours. Solvent was evaporated to give a white solid,which was stirred in water (20 ml) and methylene chloride (40 ml). Itwas washed with saturated sodium bicarbonate (2×80 ml), brine (50 ml),dried over sodium sulfate and concentrated to an white foamy solid (0.5g), which was purified by preparative HPLC (acetonitrile/water in 0.1%formic acid) to give3-[4-(4-Bromomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas an off-white solid (0.25 g, 43% yield); mp, 202-204° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 70/30 in 5 min, isocratic at 70/30 in 5 min (CH₃CN/0.1% H₃PO₄), 3.64min (98.5%). ¹H NMR (DMSO-d₆) δ 1.29-1.40 (m, 3H, CH₂, CH), 1.41-1.51(m, 5H, CH₂, CH₂, CH), 1.63 (dd, J=3.3, 12.0 Hz, 2H, CH₂), 1.81-1.93 (m,2H, CH₂), 1.94-2.04 (m, 1H, CHH), 2.08-2.21 (m, 1H, CH), 2.35-2.48 (m,5H, CHH, CH₂, CH₂), 2.53-2.63 (m, 1H, CHH), 2.75-2.99 (m, 3H, CHH, CH₂),3.42 (s, 2H, CH₂), 4.19-4.48 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H,NCH), 5.22 (s, 2H, CH₂), 7.26-7.36 (m, 3H, Ar), 7.39-7.53 (m, 3H, Ar),10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.36, 24.58, 26.08, 27.54,31.21, 45.09, 49.70, 51.56, 52.85, 61.84, 61.99, 69.44, 114.95, 115.21,127.61, 128.82, 129.81, 129.94, 133.31, 135.09, 138.56, 153.51, 168.01,170.98, 172.83. LC/MS m/e=531. Anal Calcd for C₃₁H₃₈N₄O₄ (+0.7H₂O): C,68.54; H, 7.31; N, 10.31; Found: C, 68.29; H, 7.49; N, 10.16.

5.2543-(4-{4-[4-(3-CHLORO-PHENYL)-PIPERIDIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.354 g, 0.799 mmol) was added 4-(3-chlorophenyl)piperidinehydrochloride (0.278 g, 1.198 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.396 ml, 2.396 mmol) at roomtemperature. The cloudy mixture was stirred at room temperatureovernight. Solvent was evaporated and the residue was stirred inmethylene chloride (120 ml), washed with saturated sodium bicarbonate(2×50 ml), brine (50 ml), dried over sodium sulfate, concentrated andpurified by Silica Gel Column (MeOH/CH₂Cl₂) to give3-(4-{4-[4-(3-Chloro-phenyl)-piperidin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (0.246 g, 55% yield); mp, 218-220° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 70/30 in 5 min, isocratic at 70/30 in 5 min (CH₃CN/0.1% H₃PO₄), 5.63min (95.9%). ¹H NMR (DMSO-d₆) δ 1.54-1.80 (m, 4H, CH₂, CH₂), 1.92-2.11(m, 3H, CHH, CH₂), 2.36-2.48 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH),2.83-2.99 (m, 3H, CHH, CH₂), 3.50 (s, 2H, CH₂), 4.21-4.49 (m, 2H, CH₂),5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 7.18-7.26 (m, 2H,Ar), 7.27-7.39 (m, 6H, Ar), 7.42-7.54 (m, 3H, Ar), 10.96 (s, 1H, NH).¹³C NMR (DMSO-d₆) δ 22.38, 31.21, 32.78, 41.44, 45.10, 51.59, 53.43,62.03, 69.45, 114.98, 115.23, 125.43, 125.96, 126.70, 127.62, 128.93,129.82, 129.95, 130.16, 132.97, 133.32, 135.16, 138.41, 148.83, 153.53,168.01, 170.96, 172.82. LC/MS m/e=558, 560. Anal Calcd for C₃₂H₃₂N₃O₄Cl(+0.3H₂O): C, 68.21; H, 5.83; N, 7.46; Found: C, 67.93; H, 5.64; N,7.29.

5.2553-{1-OXO-4-[4-(4-M-TOLYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.352 g, 0.794 mmol) was added 4-m-tolylpiperidine (0.209 g, 1.191mmol) and N-ethyl-N-isopropylpropan-2-amine (0.394 ml, 2.382 mmol) atroom temperature. The solution became cloudy in ˜5 minutes and wasstirred at room temperature overnight. Solvent was evaporated to give anoff-white solid, which was stirred in methylene chloride (120 ml),washed with saturated sodium bicarbonate (2×50 ml), brine (50 ml), driedand concentrated to an off-white solid. It was purified by silica gelcolumn (MeOH/CH₂Cl₂) to give3-{1-Oxo-4-[4-(4-m-tolyl-piperidin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.272 g, 63% yield); mp, 227-229° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 70/30 in 5 min, isocratic at 70/30 for 5 min (CH₃CN/0.1% H₃PO₄), 5.45min (98.6%). ¹H NMR (DMSO-d₆) δ 1.54-1.78 (m, 4H, CH₂, CH₂), 1.92-2.11(m, 3H, CHH, CH₂), 2.27 (s, 3H, CH₃), 2.36-2.48 (m, 2H, CHH, CH),2.53-2.63 (m, 1H, CHH), 2.83-2.99 (m, 3H, CHH, CH₂), 3.50 (s, 2H, CH₂),4.20-4.47 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H,CH₂), 6.95-7.07 (m, 3H, Ar), 7.12-7.20 (m, 1H, Ar), 7.29-7.39 (m, 4H,Ar), 7.41-7.54 (m, 3H, Ar), 10.96 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ21.06, 22.36, 31.21, 33.12, 41.79, 45.10, 51.59, 53.65, 62.12, 69.47,114.98, 115.23, 123.69, 126.59, 127.40, 127.64, 128.18, 128.90, 129.82,129.95, 133.32, 135.13, 137.23, 138.53, 146.17, 153.53, 168.01, 170.96,172.82. LC/MS m/e=538. Anal Calcd for C₃₃H₃₅N₃O₄: C, 73.72; H, 6.56; N,7.82; Found: C, 73.37; H, 5.53; N, 7.52.

5.2563-{1-OXO-4-[4-(4-M-TOLYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.354 g, 0.799 mmol) was added 4-(4-methoxyphenyl)piperidine (0.229 g,1.198 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.396 ml, 2.396 mmol)at room temperature. The mixture was stirred at room temperatureovernight. Solvent was evaporated and the resulting off-white solid wasstirred in methylene chloride (100 ml), washed with saturated sodiumbicarbonate (2×80 ml), brine (50 ml), dried and concentrated to anoff-white solid, which was purified by silica gel column (MeOH/CH₂Cl₂)to give3-{-Oxo-4-[4-(4-m-tolyl-piperidin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.34 g, 77% yield); mp, 189-191° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 70/30 in 5 min, isocratic at 70/30 for 5 min (CH₃CN/0.1% H₃PO₄), 5.42min (98.2%). ¹H NMR (DMSO-d₆) δ 1.51-1.77 (m, 4H, CH₂, CH₂), 1.92-2.11(m, 3H, CHH, CH₂), 2.34-2.48 (m, 2H, CHH, CH), 2.53-2.64 (m, 1H, CHH),2.82-3.01 (m, 3H, CHH, CH₂), 3.44-3.55 (m, 2H, CH₂), 3.71 (s, 3H, CH₃),4.20-4.49 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H,CH₂), 6.78-6.90 (m, 2H, Ar), 7.09-7.19 (m, 2H, Ar), 7.28-7.39 (m, 4H,Ar), 7.41-7.55 (m, 3H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ22.36, 31.21, 33.34, 40.93, 45.10, 51.59, 53.68, 54.96, 62.15, 69.47,113.68, 114.97, 115.23, 127.52, 127.62, 128.90, 129.82, 129.95, 133.32,135.13, 138.24, 138.51, 153.53, 157.49, 168.01, 170.96, 172.82. LC/MSm/e=554. Anal Calcd for C₃₃H₃₅N₃O₅: C, 71.59; H, 6.37; N, 7.59; Found:C, 71.29; H, 6.30; N, 7.57.

5.2573-(4-{4-[4-(4-CHLORO-PHENYL)-PIPERIDIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.354 g, 0.799 mmol) was added 4-(4-chlorophenyl)piperidinehydrochloride (0.278 g, 1.198 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.396 ml, 2.396 mmol) at roomtemperature. The mixture was stirred at room temperature overnight.Solvent was evaporated to an off-white solid, which was stirred inmethylene chloride (100 ml), washed with saturated sodium bicarbonate(2×80 ml), brine (80 ml), dried and concentrated to an off-white solid,which was purified by silica gel column (MeOH/CH₂Cl₂) to give3-(4-{4-[4-(4-Chloro-phenyl)-piperidin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (0.286 g, 52% yield); mp, 198-200° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, m, 1 mL/min, 240 nm, gradient from 10/90 to70/30 in 5 min, isocratic at 70/30 for 5 min (CH₃CN/0.1% H₃PO₄), 5.63min (98.9%). ¹H NMR (DMSO-d₆) δ 1.52-1.78 (m, 4H, CH₂, CH₂), 1.92-2.11(m, 3H, CHH, CH₂), 2.36-2.48 (m, 1H, CHH), 2.53-2.64 (m, 1H, CHH),2.82-3.00 (m, 3H, CHH, CH₂), 3.50 (s, 2H, CH₂), 4.20-4.49 (m, 2H, CH₂),5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 7.22-7.39 (m, 8H,Ar), 7.41-7.54 (m, 3H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ22.38, 31.21, 32.93, 41.12, 45.10, 51.58, 53.47, 62.07, 69.45, 114.98,115.23, 127.62, 128.19, 128.60, 128.90, 129.82, 129.95, 130.45, 133.32,135.14, 138.44, 145.20, 153.53, 168.01, 170.96, 172.82. LC/MS m/e=558,560. Anal Calcd for C₃₂H₃₂N₃O₄Cl (+0.1H₂O): C, 68.65; H, 5.80; N, 7.51;Found: C, 68.44; H, 5.73; N, 7.41.

5.258(S)-3-(4-((4-((4-ISOPROPYLPIPERIDIN-1-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)-3-METHYLPIPERIDINE-2,6-DIONE

(S)-3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione(500 mg, 0.765 mmol) was dissolved in acetonitrile (5 mL), and4-isopropylpiperidine (107 mg, 0.842 mmol) and DIEA (0.160 ml, 0.918mmol) were added. The mixture was stirred at room temperature for 16 h.Then, the mixture was partitioned between water (75 mL) and EtOAc (75mL), and the organic phase was washed with water (75 mL) and extractedwith 1N HCl (2×75 mL). The combined aqueous extracts were washed withEtOAc (2×75 mL), made basic (solid Na₂CO₃) and then extracted into EtOAc(2×75 mL). The combined extracts were washed with water (75 mL), dried(MgSO₄), providing the product as a white solid, 230 mg (60% yield); mp160-162° C. HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240nm, 10/90 gradient to 90/10 CH₃CN/0.1% H₃PO₄ in 10 min: 6.05 (96.32%).¹H NMR (DMSO-d₆) δ 0.84 (d, J=6.6 Hz, 6H), 0.91-1.07 (m, 1H), 1.13-1.26(m, 2H), 1.31-1.46 (m, 1H), 1.49-1.63 (m, 2H), 1.68 (s, 3H), 1.76-1.97(m, 3H), 2.52-2.91 (m, 5H), 3.43 (s, 2H), 4.55 (d, J=17.6 Hz, 1H), 4.67(d, J=17.6 Hz, 1H), 5.24 (s, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.26-7.37 (m,3H), 7.39-7.52 (m, 3H), 10.84 (s, 1H). ¹³C NMR (DMSO-d₆) δ 19.66, 20.70,27.77, 28.86, 29.01, 31.94, 41.82, 45.59, 53.65, 57.18, 62.13, 69.45,114.79, 127.67, 128.82, 129.74, 129.97, 133.91, 135.06, 138.6, 138.7,153.38, 167.00, 172.41, 173.49. Anal. Calcd for C₃₀H₃₇N₃O₄: C, 71.54%;H, 7.40%; N, 8.34%; Found: C, 71.23%; H, 7.61%; N, 8.12%.

5.2593-{1-OXO-4-[4-(4-TRIFLUOROMETHANESULFONYL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

Step 1: 4-Trifluoromethanesulfonyl-piperazine-1-carboxylic acidtert-butyl ester

To the stirred solution of tert-butyl piperazine-1-carboxylate (4.6 g,24.7 mmol) and triethylamine (4.1 ml, 29.6 mmol) in THF (50 mL) wasadded trifluoromethanesulfonyl chloride (3.1 ml, 29.6 mmol) at 0° C.through a syringe. The resulting suspension was stirred at 0° C. for 2hrs. The reaction mixture was diluted by EtOAc (100 mL) and washed withwater (50 mL), HCl (1N, aq, 50 mL), NaHCO₃ (sat. aq., 50 mL) and brine(50 mL). The organic layer was dried by MgSO₄ and concentrated undervacuo to give 4-Trifluoromethanesulfonyl-piperazine-1-carboxylic acidtert-butyl ester as clear oil (5.9 g, 87% crude yield). The compound wasput to next step without further purification; LCMS MH=319.

Step 2: 1-Trifluoromethanesulfonyl-piperazi

To the stirred solution of tert-butyl4-(trifluoromethylsulfonyl)piperazine-1-carboxylate (5.9 g, 18.54 mmol)in DCM (20 ml) was added TFA (10.00 ml, 130 mmol) at room temperature.Bubbles were evolved immediately and the reaction mixture was cooled inice/water bath. The reaction mixture was stirred at room temperature for17 hrs and the reaction mixture was added by diethyl ether (100 mL) andstirred at room temperature for 30 min. The suspension was filtered andthe white solid was washed with diethyl ether (2×25 mL). The solid (5.5g) was added by NaHCO₃ (aq, sat, 35 mL) and EtOAC (80 mL). The mixturewas extracted and the aqueous layer was extracted with EtOAc (80 mL).Organic layers were combined and dried by MgSO₄. The organic layer wasconcentrated under vacuo to give 1-Trifluoro methanesulfonyl-piperazi asa light brown oil (1.9 g, 47% yield). ¹H NMR (DMSO-d₆) δ 2.76 (t, J=5.0Hz, 4H, CH₂, CH₂), 3.36 (br. s., 4H, CH₂, CH₂); LCMS MH=219.

Step 3:3-{-Oxo-4-[4-(4-trifluoromethanesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dione

To the stirred solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(1 g, 2.2 mmol) in DCM (10 mL) at ice/water bath was added solution of1-(trifluoromethylsulfonyl)piperazine (0.640 g, 2.9 mmol) in DCM (10 mL)followed by the addition of DIPEA (0.79 ml, 4.5 mmol). The resultingsolution was kept in fridge for two days and the reaction mixture wasadded by DCM (80 mL) and water (30 mL). The mixture was extracted andorganic layer was dried by MgSO₄ and concentrated under vacuo. Theresidue was purified by ISCO to give a white solid. The solid waspurified by being stirred in diethyl ether (20 mL) to give3-{1-Oxo-4-[4-(4-trifluoromethanesulfonyl-piperazin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (700 mg, 53% yield). mp: 135-137° C.; ¹H NMR (DMSO-d₆)δ 1.91-2.04 (m, 1H, CHH), 2.34-2.48 (m, 5H, CH₂, CH₂, CHH), 2.54-2.64(m, 1H, CHH), 2.82-3.01 (m, 1H, CHH), 3.40-3.52 (m, 4H, CH₂, CH₂), 3.55(s, 2H, CH₂), 4.25 (d, J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.4 Hz, 1H,CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 7.27-7.41(m, 4H, Ar), 7.41-7.56 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆)δ 22.29, 31.11, 45.00, 46.33, 51.51, 51.80, 60.95, 69.28, 118.06 (q,J=324.6 Hz, CF₃), 114.90, 115.22, 127.62, 128.90, 129.73, 129.88,133.24, 135.45, 137.25, 153.41, 167.92, 170.89, 172.74; LCMS MH=581.

Step 4:3-(1-oxo-4-((4-((4-((trifluoromethyl)sulfonyl)piperazin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride

To the stirred mixture of3-(1-oxo-4-(4-((4-(trifluoromethylsulfonyl)piperazin-1-yl)methyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dione(680 mg, 1.17 mmol) in Acetonitrile (10 mL) was added HCl in diethylether (2 M, 1.7 ml, 3.5 mmol). The resulting suspension was stirred atroom temperature for 7 hrs and the mixture was filtered. The white solidwas washed with acetonitrile (2×10 mL) and dried under vacuum oven togive3-(1-oxo-4-((4-((4-((trifluoromethyl)sulfonyl)piperazin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione hydrochloride as a white solid (650mg, 90% yield); HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min,240 nm, 25/75, (CH₃CN/0.1% H₃PO₄), 6.53 min (99.9%); mp: 228-230° C.; ¹HNMR (DMSO-d₆) δ 1.93-2.05 (m, 1H, CHH), 2.41-2.47 (m, 1H, CHH),2.54-2.65 (m, 1H, CHH), 2.82-3.02 (m, 1H, CHH), 3.12-3.42 (m, 4H, CH₂,CH₂), 3.67-4.09 (m, 4H, CH₂, CH₂), 4.22-4.50 (m, 4H, CHH, CHH, CH₂),5.12 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.29 (s, 2H, CH₂), 7.34 (d, J=7.6Hz, 2H, Ar), 7.50 (t, J=7.9 Hz, 1H, Ar), 7.58 (d, J=7.9 Hz, 2H, Ar),7.66 (d, J=8.1 Hz, 2H, Ar), 10.98 (s, 1H, CHH), 11.83 (s, br, 1H, HCl);¹³C NMR (DMSO-d₆) δ 22.30, 31.11, 43.11, 45.00, 49.90, 51.52, 58.21,68.90, 114.86, 115.29, 119.34 (q, J=321 Hz, CF₃), 127.82, 128.95,129.77, 129.89, 131.43, 133.27, 138.00, 153.28, 167.90, 170.90, 172.77;LCMS MH=581; Anal. Calcd for C₂₆H₂₇F₃N₄O₆S+HCl+2H₂O:C, 47.82; H, 4.94;N, 8.58; Cl, 5.43; Found: C, 47.51; H, 5.01; N, 8.37; Cl, 5.24.

5.2603-{1-OXO-4-[4-(4-P-TOLYL-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.352 g, 0.794 mmol) was added 4-p-tolylpiperidine (0.209 g, 1.191mmol) and N-ethyl-N-isopropylpropan-2-amine (0.394 ml, 2.382 mmol) atroom temperature. The mixture was stirred at room temperature overnight.Solvent was evaporated and the resulting off-white solid was stirred inmethylene chloride (100 ml), washed with saturated sodium bicarbonate(2×80 ml), brine (50 ml), dried and concentrated to an off-white solid,which was purified by silica gel column (MeOH/CH₂Cl₂) to give3-{-Oxo-4-[4-(4-p-tolyl-piperidin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.144 g, 33% yield); mp, 208-210° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 jpm, 1 mL/min, 240 nm, gradient from 10/90to 70/30 in 5 min, isocratic at 70/30 for 5 min (CH₃CN/0.1% H₃PO₄), 5.60min (96.6%). ¹H NMR (DMSO-d₆) δ 1.52-1.77 (m, 4H, CH₂CH₂), 1.91-2.10 (m,3H, CHH, CH₂), 2.25 (s, 3H, CH₃), 2.36-2.48 (m, 2H, CHH, CH), 2.53-2.63(m, 1H, CHH), 2.82-3.00 (m, 3H, CHH, CH₂), 3.49 (s, 2H, CH₂), 4.20-4.48(m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H, CH₂),7.04-7.15 (m, 4H, Ar), 7.30-7.39 (m, 4H, Ar), 7.41-7.54 (m, 3H, Ar),10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 20.57, 22.36, 31.21, 33.18,41.39, 45.10, 51.58, 53.65, 62.13, 69.47, 114.98, 115.23, 126.50,127.64, 128.83, 128.90, 129.82, 129.95, 133.32, 134.81, 135.13, 138.51,143.19, 153.53, 168.01, 170.98, 172.82. LC/MS m/e=538. Anal Calcd forC₃₃H₃₅N₃O₄ (+0.2H₂O): C, 73.23; H, 6.59; N, 7.76; Found: C, 73.01; H,6.38; N, 7.54.

5.2613-{1-OXO-4-[4-(3′,4′,5′,6′-TETRAHYDRO-2′H-[3,4′]BIPYRIDINYL-1′-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₂Cl₂ solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.5 g, 1.128 mmol) was added 3-(piperidin-4-yl)pyridine (0.192 g, 1.184mmol) followed by DIPEA (0.591 ml, 3.38 mmol). The mixture was stirredat room temperature for 5 hours then was added water (15 mL) Afterextraction, the organic layer was concentrated to give a yellow solid.The solid was recrystalized from CH3CN (5 mL) to give3-{1-Oxo-4-[4-(3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a solid (200 mg, 34%). m.p: 161-163° C. LC-MS m/e=525. HPLC WatersSymmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient 5/95 to5/95 CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stay at 95/5 for 5 min:5.11 min (94%). ¹H NMR (DMSO-d₆) δ 1.57-1.80 (m, 5H, CH₂, CH₂, CH),1.89-2.15 (m, 3H, CH₂, CHH), 2.43-2.50 (m, 1H, CHH), 2.55-2.65 (m, 1H,CHH), 2.80-3.04 (m, 3H, CHH, CH₂), 3.51 (s, 2H, CH₂), 4.12-4.48 (m, 2H,CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 7.23-7.39(m, 5H, Ar), 7.40-7.54 (m, 3H, Ar), 7.67 (dt, J=1.9, 7.7 Hz, 1H, Ar),8.40 (dd, J=1.5, 4.7 Hz, 1H, Ar), 8.47 (d, J=1.9 Hz, 1H, Ar), 10.97 (s,1H, NH). ¹³C NMR (DMSO-d₆) δ 14.09, 21.30, 30.15, 31.60, 44.03, 50.52,52.38, 61.01, 68.38, 113.93, 114.17, 122.41, 126.58, 127.89, 128.77,128.90, 132.27, 133.06, 134.12, 137.34, 140.29, 146.32, 147.48, 152.46,166.96, 169.93, 171.78. Anal Calcd for C₃₁H₃₂N₄O₄:C % 70.97H % 6.15N %10.68. Found, C % 68.36H % 5.89N % 10.08.

5.262(S)-3-METHYL-3-(1-OXO-4-((4-((4-(TRIFLUOROMETHYL)PIPERIDIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1:(S)-3-(4-((4-(hydroxymethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione

A mixture of(S)-3-(4-hydroxy-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione (1.9g, 6.93 mmol), (4-(chloromethyl)phenyl)methanol (1.085 g, 6.93 mmol),potassium iodide (0.115 g, 0.693 mmol) and potassium carbonate (1.053 g,7.62 mmol) in DMF (50 mL) was stirred at room temperature for 9 days.The mixture was evaporated under vacuum. To the residue was added water(150 mL) and EtOAc (150 mL), and the resulting suspension was stirredfor 16 h. The suspension was filtered, and the filter was rinsed withwater (50 mL) and EtOAc (2×50 mL). The organic phase was washed with 10%aqueous sodium carbonate solution (2×75 mL), 1N HCl (100 mL), and brine(100 mL), was dried (MgSO₄) and evaporated. The residue was combinedwith the solid precipitate that had been filtered off, to afford a totalof 2.09 g of a crude product.

Step 2:(S)-4-(((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzylmethanesulfonate

The residue was suspended in 50 mL of acetonitrile and the mixture wascooled to 0° C. Methanesulfonyl chloride (0.538 mL, 6.93 mmol) and DIEA(1.448 ml, 8.31 mmol) were added, and the mixture stirred at 0° C. for30 min. Then, the mixture was quenched by the addition of AcOH (0.5 mL)and then water (5 mL), and was evaporated. The residue was partitionedbetween EtOAc (125 mL) and brine (125 mL). A solid that did not dissolvein either phase was filtered off, and the phases were separated. Thesolid was combined with the organic layer and evaporated. The residuewas chromatographed using a methylene chloride-acetonitrile gradient.The product eluted at ˜40% ACN. The yield after drying was 1.3 g (40%over the two steps); ¹H NMR (DMSO-d₆) δ 1.69 (s, 3H), 1.82-1.95 (m, 1H),2.52-2.83 (m, 3H), 3.24 (s, 3H), 5.27 (s, 2H), 5.30 (s, 2H), 7.17-7.35(m, 2H), 7.39-7.62 (m, 5H), 10.85 (s, 1H).

Step 3:(S)-3-methyl-3-(-oxo-4-((4-((4-(trifluoromethyl)piperidin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione

A mixture of(S)-4-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzylmethanesulfonate (0.40 g, 0.847 mmol) and 4-(trifluoromethyl)piperidinehydrochloride (0.161 g, 0.847 mmol) was cooled to 0° C., and then DIEA(0.310 ml, 1.778 mmol) was added. After 6 h, the rxn was evaporatedunder vacuum, and the residue was dissolved partitioned between EtOAc(50 mL) and water (50 mL), and the aqueous phase was extracted withEtOAc (50 mL). The combined organic fractions were extracted with 1N HCl(2×50 mL). The combined aqueous extracts were washed with EtOAc (50 mL),and then made basic using 10% aqueous sodium carbonate. This mixture wasthen extracted with EtOAc (2×50 mL), and the combined extracts werewashed with brine (100 mL), dried (MgSO₄), and evaporated under vacuum,providing 0.39 g as a white solid, in 87% yield; mp 168-170° C. HPLC:Waters X-Terra, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 5/95 to 95/5CH₃CN-0.1% NH₄(HCO₂) over 5 min then 10 min 95/5 CH₃CN-0.1% NH₄(HCO₂):5.73 (100%). ¹H NMR (DMSO-d₆) δ 1.33-1.54 (m, 2H), 1.68 (s, 3H),1.73-1.81 (m, 2H), 1.83-2.04 (m, 3H), 2.16-2.35 (m, 1H), 2.51-2.80 (m,3H), 2.81-2.95 (m, 2H), 3.48 (s, 2H), 4.56 (d, J=17.6 Hz, 1H), 4.68 (d,J=17.6 Hz, 1H), 5.24 (s, 2H), 7.23 (d, J=7.4 Hz, 1H), 7.27-7.37 (m, 3H),7.40-7.52 (m, 3H), 10.85 (s, 1H). ¹³C NMR (DMSO-d₆) δ 20.68, 24.24,27.77, 28.99, 38.93, (q, J=38.9 Hz), 45.59, 51.43, 57.18, 61.62, 69.41,114.79, 114.81, 127.71, 127.87 (q, J=278 Hz), 128.82, 129.74, 129.97,133.91, 135.22, 138.18, 153.38, 167.00, 172.39, 173.47. Anal. Calcd forC₂₈H₃₀F₃N₃O₄+0.3H₂O: C, 62.87%; H, 5.77%; N, 7.85%; Found: C, 62.87%; H,5.67%; N, 7.86%.

5.263(S)-3-(4-((4-((4,4-DIMETHYLPIPERIDIN-1-YL)METHYL)BENZYOXY)-1-OXOISOINDOLIN-2-YL)-3-METHYLPIPERIDINE-2,6-DIONE

A mixture of(S)-4-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzylmethanesulfonate (0.33 g, 0.698 mmol) and 4,4-dimethylpiperidinehydrochloride (0.105 g, 0.698 mmol) was cooled to 0° C., and then DIEA(0.255 ml, 1.467 mmol) was added. After 16 h, the mixture was evaporatedunder vacuum. The residue was partitioned between EtOAc (100 mL) andwater (100 mL), and the aqueous phase was extracted with EtOAc (100 mL).The combined organic phases were extracted with 1N HCl (2×75 mL), andthe combined extracts were wash with EtOAc (100 mL) and then made basicusing solid sodium carbonate. The aqueous mixture was then extractedwith EtOAc (2×75 mL), and the combined extracts were washed with water(100 mL), dried (MgSO₄), and evaporated, providing the product as awhite solid, 250 mg, in 73% yield; mp 158-160° C. HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 10/90 gradient to 90/10CH₃CN/0.1% H₃PO₄ in 10 min then 90/10 CH₃CN/0.1% H₃PO₄ for 5 min: 5.79(95.52%). ¹H NMR (DMSO-d₆) δ 0.89 (s, 6H), 1.20-1.38 (m, 4H), 1.68 (s,3H), 1.81-1.94 (m, 1H), 2.22-2.41 (m, 4H), 2.53-2.83 (m, 3H), 3.46 (s,2H), 4.56 (d, J=17.6 Hz, 1H), 4.61-4.75 (m, J=17.8 Hz, 1H), 5.23 (s,2H), 7.22 (d, J=7.4 Hz, 1H), 7.26-7.37 (m, 3H), 7.38-7.50 (m, 3H), 10.85(s, 1H). ¹³C NMR (DMSO-d₆) δ 20.68, 27.77, 28.04, 28.18, 28.99, 38.32,45.59, 49.38, 57.18, 62.09, 69.45, 114.78, 114.79, 127.67, 128.79,129.72, 129.97, 133.89, 135.03, 138.76, 153.38, 167.00, 172.39, 173.47.Anal. Calcd for C₂₉H₃₅N₃O₄+0.3H₂O: C, 70.36%; H, 7.25%; N, 8.49%; Found:C, 70.41%; H, 7.18%; N, 8.41%.

5.2643-(4-((4-((4-ETHYL-3-OXOPIPERAZIN-1-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

A solution of 1-ethylpiperazin-2-one hydrochloride (83 mg, 0.496 mmol)and DIEA (0.276 mL, 1.579 mmol) in dry MeCN (5 mL, 96 mmol) was added to3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.451 mmol). The resulting solution (pale amber) was stirred at40° C. for 1 h. The mixture was extracted with ethyl acetate and 1NNaHCO₃. The organic layer was washed with brine and dried (Na₂SO₄),filtered, and concentrated in vacuo to give3-(4-((4-((4-ethyl-3-oxopiperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (169 mg, 76% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 7.41 min (99.5%);mp: 163-165° C.; ¹H NMR (DMSO-d₆) δ 1.01 (t, J=7.2 Hz, 3H, CH₃),1.87-2.08 (m, 1H, CHH), 2.34-2.48 (m, 1H, CHH), 2.52-2.68 (m, 3H, CH₂,CHH), 2.81-3.02 (m, 1H, CHH), 2.94 (s, 2H, CH₂), 3.17-3.31 (m, 4H, CH₂,CH₂), 3.53 (s, 2H, CH₂), 4.25 (d, J=17.4 Hz, 1H, CHH), 4.42 (d, J=17.6Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.24 (s, 2H, CH₂),7.24-7.40 (m, 4H, Ar), 7.41-7.61 (m, 3H, Ar), 10.96 (s, 1H, NH). ¹³C NMR(DMSO-d₆) δ 11.89, 22.33, 31.16, 45.07, 45.17, 48.86, 51.56, 56.81,60.27, 69.36, 114.97, 115.22, 127.70, 128.95, 129.78, 129.93, 133.28,135.52, 137.15, 153.48, 165.23, 167.97, 170.93, 172.78; One carbonsignal is overlapped with DMSO; LCMS: MH=491; Anal Calcd forC₂₇H₃₀N₄O₅+0.35H₂O: C, 65.27; H, 6.23; N, 11.28; Found: C, 65.27; H,6.25; N, 11.06.

5.2653-(4-((4-((4-BUTYL-3-OXOPIPERAZIN-1-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.451 mmol) in dry MeCN (5 mL, 96 mmol), was added1-butylpiperazin-2-one (82 mg, 0.496 mmol) and DIEA (0.158 mL, 0.902mmol). The yellowish clear solution was stirred at room temperature for3 h. The crude mixture in ethyl acetate was extracted with 1N NaHCO₃,then brine. The organic layer was dried (Na₂SO₄), filtered, andconcentrated in vacuo to give3-(4-((4-((4-butyl-3-oxopiperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (160 mg, 68% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 6.52 min (99.5%);mp: 138-140° C.; ¹H NMR (DMSO-d₆) δ 0.88 (t, J=7.2 Hz, 3H, CH₃),1.14-1.33 (m, 2H, CH₂), 1.36-1.55 (m, 2H, CH₂), 1.88-2.05 (m, 1H, CHH),2.34-2.47 (m, 1H, CHH), 2.52-2.68 (m, 3H, CH₂, CHH), 2.80-3.01 (m, 3H,CH₂, CHH), 3.17-3.29 (m, 4H, CH₂, CH₂), 3.53 (s, 2H, CH₂), 4.25 (d,J=17.6 Hz, 1H, CHH), 4.42 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2Hz, 1H, CH), 5.24 (s, 2H, CH₂), 7.25-7.41 (m, 4H, Ar), 7.42-7.57 (m, 3H,Ar), 10.96 (s, 1H, NH); 13C NMR (DMSO-d₆) δ 13.64, 19.44, 22.33, 28.41,31.16, 44.85, 45.07, 45.73, 48.88, 51.56, 56.81, 60.27, 69.36, 114.97,115.22, 127.70, 128.95, 129.78, 129.95, 133.30, 135.53, 137.13, 153.48,165.48, 167.97, 170.95, 172.80; LCMS: MH=519; Anal Calcd forC₂₇H₃₀N₄O₅+0.6H₂O: C, 65.79; H, 6.70; N, 10.58; Found: C, 65.76; H,6.59; N, 10.56.

5.2663-(1-OXO-4-((4-((4-(PYRIMIDIN-2-YL)PIPERAZIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

A mixture of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(205 mg, 0.462 mmol) in MeCN (8 mL) was stirred at room temperature. Tothe solution was added 2-(piperazin-1-yl)pyrimidine (81 mg, 0.495 mmol),followed by DIEA (0.145 mL, 0.832 mmol). The mixture was kept at roomtemperature for 4 h. The crude rxn mixture was diluted with EtOAc. Theorganic layer was washed with 1N NaHCO₃ (2×25 mL), brine and dried overNa₂SO₄. The solvent was removed in vacuo to give3-(1-oxo-4-((4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (244 mg, 100% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 4.26 min (97.3%),mp: 142-144° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.06 (m, 1H, CHH), 2.41 (t,J=4.9 Hz, 4H, CH₂, CH₂), 2.47 (br. s., 1H, CHH), 2.53-2.63 (m, 1H, CHH),2.83-2.99 (m, 1H, CHH), 3.52 (s, 2H, CH₂), 3.72 (t, J=4.7 Hz, 4H, CH₂,CH₂), 4.26 (d, J=17.6 Hz, 1H, CHH), 4.43 (d, J=17.6 Hz, 1H, CHH), 5.11(dd, J=5.2, 13.1 Hz, 1H, CH), 5.24 (s, 2H, CH₂), 6.61 (t, J=4.7 Hz, 1H,Pyr), 7.27-7.39 (m, 4H, Ar), 7.42-7.55 (m, 3H, Ar), 8.34 (d, J=4.7 Hz,2H, Pyr), 10.97 (s, 1H, NH). See ˜0.15 eq. of EtOAc in H-NMR. ¹³C NMR(DMSO-d₆) δ 22.33, 31.16, 43.26, 45.07, 51.56, 52.35, 61.72, 69.39,110.01, 114.96, 115.20, 127.64, 128.94, 129.78, 129.93, 133.30, 135.30,137.89, 153.49, 157.82, 161.16, 167.97, 170.95, 172.80; LCMS: MH=527;Anal Calcd for C₂₉H₃₀N₆O₄+0.49H₂O+0.15 EtOAc: C, 64.80; H, 5.91; N,15.32; Found: C, 64.80; H, 5.75; N, 15.32.

5.2673-(1-OXO-4-((4-((3-OXO-4-(PYRIDIN-2-YL)PIPERAZIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a suspensionof(S)-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.451 mmol) and 1-(pyridin-2-yl)piperazin-2-one dihydrochloride(124 mg, 0.496 mmol) in dry MeCN (5 mL), was added DIEA (0.276 mL, 1.579mmol). The solids dissolved with agitation to give a yellow solutionwhich was warmed up to 40° C. for 3 days. The reaction mixture wasdiluted with EtOAc (˜150 mL) and washed with 1 N NaHCO₃ (2×30 mL) andbrine. The clear organic layer was dried over Na₂SO₄, filtered, andconcentrated in vacuo to give a glassy residue. The residue was treatedwith water (30 mL) and the mixture was sonicated extensively to give awell-dispersed solid that was collected by filtration and washed withadditional water (˜45 mL). The cake was slurried in Et₂O, trituratedwith aid of a spatula, and then filtered. This process was repeated 4times (total Et₂O filtrate volume ˜125 mL). The cake was suction driedand then dried in a vacuum oven to give an off-white solid (143 mg). Thesolid was dissolved in DMF (10 mL) and purified using reversed-phasepreparatory HPLC. The product was eluted with an acetonitrile/watergradient (0.1% formic acid in both mobile phases, 5% to 80% MeCN over 20minutes) and fractions were collected by mass trigger. The desiredfractions were combined and concentrated in vacuo and the residue wastreated with water and sonicated to give a white slurry. The solid wasfiltered and then dried in a vacuum oven at 50° C. overnight to give3-(l-oxo-4-((4-((3-oxo-4-(pyridin-2-yl)piperazin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (72 mg, 30% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 4.98 min (97.9%);mp: 224-226° C.; ¹H NMR (DMSO-d₆) δ 1.85-2.05 (m, 1H, CHH), 2.35-2.48(m, 1H, CHH), 2.57 (d, J=18.3 Hz, 1H, CHH), 2.80 (t, J=5.0 Hz, 2H, CH₂),2.84-3.00 (m, 1H, CHH), 3.23 (s, 2H, CH₂), 3.64 (s, 2H, CH₂), 3.87 (t,J=5.4 Hz, 2H, CH₂), 4.26 (d, J=17.6 Hz, 1H, CHH), 4.43 (d, J=17.6 Hz,1H, CHH), 5.11 (dd, J=5.2, 13.1 Hz, 1H, CH), 5.25 (s, 2H, CH₂), 7.22(ddd, J=2.3, 4.9, 6.0 Hz, 1H, Ar), 7.33 (dd, J=1.6, 7.8 Hz, 2H, Ar),7.37-7.44 (m, 2H, Ar), 7.44-7.55 (m, 3H, Ar), 7.74-7.88 (m, 2H, Ar),8.44 (dt, J=1.4, 4.7 Hz, 1H, Ar), 10.96 (s, 1H, NH); 3C NMR (DMSO-d₆) δ22.33, 31.16, 45.07, 46.11, 48.89, 51.56, 57.64, 60.09, 69.38, 114.99,115.23, 119.62, 120.83, 127.74, 129.01, 129.80, 129.95, 133.30, 135.62,136.99, 137.31, 147.70, 153.07, 153.48, 166.92, 167.97, 170.95, 172.80;LCMS: MH=540; Anal Calcd for C₃₀H₂₉N₅O+0.49H₂O+0.15 EtOAc: C, 64.80; H,5.91; N, 15.31; Found: C, 64.80; H, 5.75; N, 15.32.

5.2683-(1-OXO-4-((4-((4-(2,2,2-TRIFLUOROETHYL)PIPERAZIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

A 20-mL reaction vial was charged with(S)-3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(307 mg, 0.693 mmol), 1-(2,2,2-trifluoroethyl)piperazine (170 mg, 0.706mmol), and catalytic tetrabutylammonium bromide (22.33 mg, 0.069 mmol).To the mixture was added dry MeCN (5 mL) followed by DIEA (0.423 mL,2.424 mmol). Agitation resulted in a clear yellow solution that stirredat room temperature overnight. The crude mixture was partitioned betweenEtoAc (˜150 mL) and 1N NaHCO₃ (˜50 mL). The organic layer was washedtwice more with 1 N NaHCO₃ (2×35 mL) and brine, dried (Na₂SO₄), andconcentrated in vacuo to give a glassy solid. Et₂O (˜30 mL) was addedand the mixture was sonicated extensively until a well-dispersed slurrywas obtained. To the mixture, n-hexanes (˜30 mL) were added withintermittent sonication to further break up remaining solid aggregates.The mixture was stirred at room temperature overnight and then filteredon a medium fritted funnel with suction. Residual solid in flask wastransferred to funnel with more n-hexanes (˜30 mL). The solid wassuction dried and then triturated with H₂O (20 mL). The remaining solidwas collected on a filter funnel and the cake washed with water (˜250mL), suction dried, and then dried further in vacuum oven at 50° C. togive3-(1-oxo-4-((4-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dioneas a pale yellow solid (262 mg, 71% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 22/78 CH₃CN/0.1% H₃PO₄, 4.49 min(94.7%); mp: 133-135° C.; ¹H NMR (DMSO-d₆) δ 1.88-2.05 (m, 1H, CHH),2.22-2.48 (m, 5H, CH₂, CH₂, CHH), 2.52-2.71 (m, 5H, CH₂, CH₂, CHH),2.82-3.02 (m, 1H, CHH), 3.13 (q, J=10.3 Hz, 2H, CH₂CF₃), 3.46 (s, 2H,CH₂N), 4.25 (d, J=17.4 Hz, 1H, lactam CHH), 4.42 (d, J=17.6 Hz, 1H,lactam CHH), 5.11 (dd, J=4.9, 13.2 Hz, 1H, alpha-CH), 5.22 (s, 2H,CH₂O), 7.26-7.39 (m, 4H, Ar), 7.40-7.56 (m, 3H, Ar), 10.97 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 45.06, 51.55, 52.42, 53.06, 56.81 (q,J=29.7 Hz, CCF₃), 61.56, 69.39, 114.96, 115.20, 125.90 (q, J=280.6 Hz,CF₃), 127.58, 128.85, 129.78, 129.93, 133.28, 135.21, 137.95, 153.49,167.97, 170.95, 172.80. Outer signals of quartet at 125.90 are too weakto be observed. LCMS: MH=531; Anal Calcd for C₂₇H₂₉F₃N₄O₄.+0.24H₂O: C,60.63; H, 5.56; N, 10.47; F, 10.66; Found: C, 60.64; H, 5.49; N, 10.20;F, 9.56.

5.2693-(1-OXO-4-((4-(((S)-2-(TRIFLUOROMETHYL)PIPERIDIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

In a 20-mL reaction vial,(S)-3-(4-(4-(bromomethyl)benzyloxy)oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.790 mmol) was dissolved in dry MeCN (5 m). To the solutionwas added (S)-2-(trifluoromethyl)piperidine (140 mg, 0.916 mmol)followed by DIEA (0.345 mL, 1.974 mmol). The mixture was stirred at roomtemperature for 15 h and then at 70° C. for 8 h overnight. The reactionmixture was partitioned between EtOAc (˜100 mL) and water (˜25 mL). Theorganic layer was washed with 1 N NaHCO₃ (˜75 mL) and brine, dried(Na₂SO₄), and concentrated in vacuo to give a white solid. The solid wasdissolved in DMF (8 mL), passed through a syringe filter, and thefiltrate injected onto a reversed-phase preparatory HPLC. The productwas eluted with an acetonitrile/water gradient (0.1% formic acid in bothmobile phases, 5% to 95% MeCN over 20 minutes) and fractions werecollected by mass trigger. The desired fractions were combined andconcentrated in vacuo to remove all the MeCN and most of the water,producing a white slurry (˜20 mL). The solid was collected byfiltration, the cake suction dried, and then dried in a vacuum oven at50° C. for 5 h to give3-(1-oxo-4-((4-(((S)-2-(trifluoromethyl)piperidin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (506 mg, 51% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3:9×150 mm, 1 ml/min, 240 nm, 45/55 CH₃CN/0.1% H₃PO₄, 3.46 min (97.6%);mp: 120-122; ¹H NMR (DMSO-d₆) δ 1.38-1.63 (m, 4H, CH₂, CH₂), 1.67-1.90(m, 2H, CH₂), 1.91-2.05 (m, 1H, CHH), 2.36-2.48 (m, 2H, CHH, CHH),2.53-2.62 (m, 1H, CHH), 2.64-2.78 (m, 1H, CHH), 2.82-2.99 (m, 1H, CHH),3.46 (qt, J=4.9, 9.5 Hz, 1H, CHCF₃), 3.84 (s, 2H, CH₂), 4.25 (d, J=17.4Hz, 1H, CHH), 4.42 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.2, 13.1 Hz,1H, CH), 5.23 (s, 2H, CH₂), 7.29-7.39 (m, 4H, Ar), 7.41-7.54 (m, 3H,Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 19.64, 22.31, 22.94, 31.16,45.06, 46.15, 51.55, 58.03 (q, J=24.2 Hz, CCF₃), 57.84, 69.39, 114.94,115.20, 126.02, 127.70, 128.14, 129.78, 129.87, 129.95, 133.28, 135.25,139.12, 153.49, 167.97, 170.95, 172.80. CF₃ quartet is not assigned. Onecarbon signal in aliphatic region is not observed; possibly overlappedwith another signal; LCMS: MH=516; Anal Calcd for C₂₇H₂₈F₃N₃O₄′+0.5H₂O:C, 61.83; H, 5.57; N, 8.01; F, 10.87; Found: C, 61.92; H, 5.48; N, 7.94;F, 10.08.

5.2703-(4-{4-[4-(3,5-DIFLUORO-PHENYL)-PIPERIDIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE,HYDROCHLORIDE

To the CH₂Cl₂ solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.790 mmol) was added DIPEA (0.414 ml, 2.369 mmol) and4-(3,5-difluorophenyl)piperidine (156 mg, 0.790 mmol) at roomtemperature. The mixture was stirred at room temperature overnight,added water (20 mL) and extracted. The organic layer was concentratedand the resulted solid was purified on silica gel column eluted withCH₂Cl₂/MeOH to give a white solid. The solid was dissolved in CH₂Cl₂ (20mL) and to it was added 3 mL of HCl (2.0M in ether). The mixture wasstirred at room temperature for 1 hour. The resulted suspension wasfiltered to give3-(4-{4-[4-(3,5-difluoro-phenyl)-piperidin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione,hydrochloride as a white solid (0.27 g, 61%). Melting point: 281-283°C.LC-MS m/e=560. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1mL/min, 240 nm, gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂O during 5min and stay at 95/5 for 5 min: 7.05 min (98.6%). ¹H NMR (DMSO-d₆) δ1.89-2.14 (m, 5H, CH₂, CH₂, CHH), 2.36-2.45 (m, 1H, CHH), 2.55-2.64 (m,1H, CHH), 2.79-2.95 (m, 2H, CHH), 2.95-3.10 (m, J=18.5 Hz, 2H, CH₂),3.42 (d, J=11.9 Hz, 2H, CH₂), 4.22-4.50 (m, 4H, CH₂, CH₂), 5.12 (dd,J=5.1, 13.2 Hz, 1H, NCH), 5.31 (s, 2H, CH₂), 6.96 (dd, J=2.1, 8.9 Hz,2H, Ar), 7.04-7.16 (m, 1H, Ar), 7.29-7.38 (m, 2H, Ar), 7.43-7.54 (m, 1H,Ar), 7.55-7.69 (m, 4H, Ar), 10.66 (br. s., 1H, HCl), 10.97 (s, 1H, NH).¹³C NMR (DMSO-d₆) δ 22.40, 29.02, 31.21, 38.24, 45.09, 51.30, 51.61,58.65, 69.03, 101.73, 102.06, 102.40, 109.69, 109.79, 109.91, 110.01,115.00, 115.39, 127.85, 128.03, 129.36, 129.85, 129.98, 131.09, 131.63,133.38, 138.07, 148.79, 148.91, 153.37, 160.92, 164.00, 164.17, 167.96,170.98, 172.83; Anal Calcd for C₃₂H₃₁F₂N₃O₄ HCl+1.3H₂O, C: 62.04; H:5.63%; N: 6.78%; Found: C: 61.73; H: 5.56%; N: 6.72%.

5.2713-(4-{4-[4-(2,4-DIFLUORO-PHENYL)-PIPERIDIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONEHYDROCHLORIDE

To the CH₂Cl₂ solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.790 mmol) and 4-(2,4-difluorophenyl)piperidine (171 mg, 0.869mmol) was added N-ethyl-N-isopropylpropan-2-amine (0.422 ml, 2.369mmol). The mixture was stirred at room temperature for 4 hours. Water(15 mL) was added to the reaction mixture and extracted. The organiclayer was concentrated and the solid was dissolved in CH₂Cl₂. Thesolution was added HCl (2 mL, 2.0 M in ether) and stirred for 1 hours.The suspension was filtered to give3-(4-{4-[4-(2,4-Difluoro-phenyl)-piperidin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dionehydrochloride as a white solid (0.18 g, 40%). Melting point: 274-276° C.LC-MS m/e=560. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min,240 nm, gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂O during 5 min andstay at 95/5 for 5 min: 7.03 min (94%). ¹H NMR (DMSO-d₆) δ 1.81-2.21 (m,5H, CH₂, CH₂, CH), 2.35-2.48 (m, 1H, CHH), 2.53-2.66 (m, 1H, CHH),2.82-2.99 (m, 1H, CHH), 3.09 (d, J=10.0 Hz, 3H, CH₂, CHH), 3.42 (d,J=11.7 Hz, 2H, CH₂), 4.22-4.50 (m, 4H, CH₂, CH₂), 5.12 (dd, J=4.9, 13.2Hz, 1H, CHN), 5.31 (s, 2H, CH₂), 7.04-7.15 (m, 1H, Ar), 7.16-7.27 (m,1H, Ar), 7.27-7.37 (m, 2H, Ar), 7.44-7.54 (m, 1H, Ar), 7.56-7.67 (m, 3H,Ar), 10.52 (br. s., 1H, HCl), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.40, 28.37, 31.21, 32.04, 45.09, 51.48, 51.61, 58.84, 69.03, 103.60,103.95, 104.30, 111.58, 111.83, 115.00, 115.39, 127.85, 128.73, 128.85,128.93, 129.36, 129.85, 129.98, 131.62, 133.38, 138.09, 153.37, 161.62,167.96, 170.98, 172.83; Anal Calcd for C₃₂H₃₁F₂N₃O₄ HCl+0.8H₂O; C:62.96%; H: 5.55%; N: 6.88%; Found: C: 62.83%, H: 5.38%; N: 6.87%.

5.272 3-(1-OXO-4-{4-[4-(2,2,2-TRIFLUORO-ACETYL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the stirred solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300 mg, 0.68 mmol) in DCM (7 mL) at room temperature was added thesolution of 2,2,2-trifluoro-1-(piperazin-1-yl)ethanone (185 mg, 1.0mmol) in DCM (1 mL) followed by the addition of DIPEA (0.236 ml, 1.4mmol). The resulting solution was stirred at room temperature for 7.5hrs and the reaction mostly completed. The reaction mixture was added byDCM (30 mL) and water (20 mL). The mixture was extracted. The organiclayer was dried by MgSO₄ and concentrated under vacuo. The residue waspurified by ISCO to give a white solid which was further purified bybeing stirred in EtOAc (3 mL) to give3-(1-Oxo-4-{4-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-ylmethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (180 mg, 49% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 m, 1 mL/min, 240 nm, 20/80, (CH₃CN/0.1% H₃PO₄), 5.21 min(99.9%); mp: 125-127° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.05 (m, 1H, CHH),2.38-2.48 (m, 5H, CHH, CH₂, CH₂), 2.53-2.65 (m, 1H, CHH), 2.85-3.01 (m,1H, CHH), 3.47-3.70 (m, 6H, CH₂, CH₂, CH₂), 4.17-4.55 (m, 2H, CHH, CHH),5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 7.33 (dd, J=4.1,7.8 Hz, 4H, Ar), 7.40-7.56 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 21.82, 30.65, 42.42, 44.54, 44.81, 51.02, 51.14, 51.81,60.57, 68.81, 114.43, 114.70, 127.15, 128.45, 129.28, 129.41, 132.78,134.93, 136.90, 152.96, 167.46, 170.44, 172.29; LCMS MH=545; Anal. Calcdfor C₂₇H₂₇F₃N₄O₅+0.3H₂O: C, 58.97; H, 5.06; N, 10.19; Found: C, 58.85;H, 4.82; N, 10.03.

5.2733-(4-{4-[4-(4-FLUORO-PHENYL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE, DIHYDROCHLORIDE

To the CH₂Cl₂ solution of3-(4-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.23 g, 0.424 mmol) and 1-(4-fluorophenyl)piperazine (142 mg, 0.790mmol) was added N-ethyl-N-isopropylpropan-2-amine (422 μl, 2.369 mmol).The mixture was stirred at room temperature overnight. The reactionmixture was added water (15 mL) and extracted. The organic layer wasconcentrated and the resulted solid was dissolved in CH₂Cl₂ (35 mL) and2M HCl in ether was added dropwise. The mixture was stirred at roomtemperature for 2 hours. The suspension was filtered to give3-(4-{4-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, dihydrochloride as whitesolid (230 mg, 54%). Melting point: 191-193° C. LC-MS m/e=543. HPLCWaters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stay at 95/5 for 5min: 6.67 min (96%). ¹H NMR (DMSO-d₆) δ 1.80-2.09 (m, 1H, CHH),2.36-2.45 (m, J=4.3 Hz, 1H, CHH), 2.58 (d, J=18.5 Hz, 1H, CHH),2.81-3.00 (m, 1H, CHH), 3.16 (d, J=8.9 Hz, 4H, CH₂, CH₂), 3.34 (d, J=8.1Hz, 2H, CH₂), 3.63-3.80 (m, 2H, CH₂), 4.15-4.62 (m, 4H, CH₂, CH₂), 5.12(dd, J=5.1, 13.2 Hz, 1H, CHN), 5.30 (s, 2H, CH₂), 6.89-7.06 (m, 2H, Ar),7.04-7.16 (m, 2H, Ar), 7.26-7.42 (m, 2H, Ar), 7.42-7.55 (m, 1H, Ar),7.54-7.64 (m, 2H, Ar), 7.64-7.79 (m, 2H, Ar), 10.97 (s, 1H, nh), 11.46(br. s., 1H, HCl); ¹³C NMR (DMSO-d₆) δ 22.39, 31.21, 45.10, 45.91,50.16, 51.61, 58.05, 69.03, 114.98, 115.36, 115.65, 117.78, 117.88,127.85, 129.24, 129.85, 130.00, 131.69, 133.37, 138.06, 146.34, 153.37,154.99, 158.12, 167.98, 170.96, 172.83; Anal Calcd for C₃₁H₃₁FN₄O₄+1.8HCl+2H₂O: C: 57.79%; H: 5.76%; N: 8.70%; Cl: 9.90%; Found: C: 57.61%, H:5.64%; N: 8.60%, Cl: 9.54%.

5.2743-(4-{4-[4-(4-FLUORO-BENZYL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.40 g, 0.902 mmol) was added 1-(4-fluorobenzyl)piperazine (0.193 g,0.993 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.298 ml, 1.805mmol). The solution was stirred at room temperature for two hours. Water(20 ml) was added to the reaction solution and extracted with methylenechloride (2×30 ml), washed with brine, evaporated and the off-whitesolid was purified by silica gel column (MeOH/CH₂Cl₂) to give3-(4-{4-[4-(4-Fluoro-benzyl)-piperazin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (0.336 g, 66.9% yield); mp, 222-224° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 m, 1 mL/min, 240 nm, gradient from 10/90 to95/05 in 5 min, isocratic at 95/05 for 5 min (CH₃CN/0.1% H₃PO₄), 4.67min (97.01%). ¹H NMR (DMSO-d₆) δ 1.92-2.04 (m, 1H, CHH), 2.20-2.47 (m,8H, 2CHH, 3CH₂), 2.55-2.66 (m, 1H, CHH), 2.82-3.01 (m, 1H, CHH),3.30-3.35 (m, 2H, CH₂), 3.45 (s, 2H, CH₂), 4.19-4.47 (m, 2H, CH₂), 5.11(dd, J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.07-7.17 (m, 2H, Ar),7.26-7.37 (m, 6H, Ar), 7.40-7.53 (m, 3H, Ar), 10.97 (s, 1H, NH). ¹³C NMR(DMSO-d₆) δ 22.36, 31.21, 45.10, 51.59, 52.48, 52.58, 61.08, 61.71,69.44, 114.68, 114.95, 115.23, 127.62, 128.86, 129.81, 129.95, 130.55(d, J_(C-F)=10), 133.31, 134.37, 135.19, 138.12, 153.51, 161.17 (d,J_(C-F)=250), 168.01, 170.96, 172.82. LC/MS m/e=557. Anal Calcd forC₃₂H₃₃N₄O₄F: C, 69.05; H, 5.98; N, 10.07; Found: C, 68.93; H, 5.99; N,10.01.

5.2753-(1-OXO-4-{4-[4-(2,2,2-TRIFLUORO-ETHANESULFONYL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

Step 1: 4-(2,2,2-Trifluoro-ethanesulfonyl)-piperazine-1-carboxylic acidtert-butyl ester

To the stirred solution of tert-butyl piperazine-1-carboxylate (0.850 g,4.56 mmol) and TEA (0.76 ml, 5.48 mmol) in THF (10 mL) at 0° C. wasadded 2,2,2-trifluoroethane sulfonyl chloride (1.0 g, 5.48 mmol) in THF(0.5 mL). The resulting suspension was stirred at 0° C. for 1.5 hrs andthe reaction mixture was diluted by EtOAC (30 mL). The mixture waswashed with water (15 mL), HCl (1N, aq, 15 mL) and NaHCO₃ (15 mL) andbrine (20 mL). Organic layer was dried by MgSO₄ and concentrated undervacuo to give 4-(2,2,2-Trifluoro-ethanesulfonyl)-piperazine-1-carboxylicacid tert-butyl ester as a white solid (1.3 g, 86% yield). The compoundwas put to next step without further purification. ¹H NMR (DMSO-d₆) δ1.41 (s, 9H, tButyl), 3.12-3.26 (m, 4H, CH₂, CH₂), 3.36-3.48 (m, 4H,CH₂, CH₂), 4.52 (q, J=10.1 Hz, 2H, CH₂); LCMS MH (without boc)=233.

Step 2: 1-(2,2,2-Trifluoro-ethanesulfonyl)-piperazine

To the stirred solution of tert-butyl4-(2,2,2-trifluoroethylsulfonyl)piperazine-1-carboxylate (1.3 g, 3.9mmol) in DCM (20 mL) at room temperature was added TFA (3.0 mL, 39.1mmol). The resulting solution was stirred at room temperature 15 hrs andthe reaction mixture was diluted by DCM (30 mL) and added by NaHCO₃(sat., aq, 15 mL) slowly to control the gas emission. The resultingmixture was stirred at room temperature for 10 mins and partitioned. Theorganic layer was washed with NaHCO₃ (sat., aq, 5 mL) and brine (20 mL).The combined aqueous layer was extracted with DCM (4×40 mL). Combinedlayers were dried by MgSO₄ and concentrated under vacuo to give1-(2,2,2-Trifluoro-ethanesulfonyl)-piperazine as white solid (930 mg,102% crude yield). ¹H NMR (DMSO-d₆) δ 2.41 (br. s., 1H, NH), 2.64-2.85(m, 4H, CH₂, CH₂), 3.02-3.20 (m, 4H, CH₂, CH₂), 4.46 (q, J=10.2 Hz, 2H,CH₂); LCMS MH=233.

Step 3:3-(1-Oxo-4-{4-[4-(2,2,2-trifluoro-ethanesulfonyl)-piperazin-1-ylmethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione

To the stirred mixture of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (350 mg, 0.79 mmol) and1-(2,2,2-trifluoroethylsulfonyl) piperazine (183 mg, 0.79 mmol) in DCM(10 mL) was added DIPEA (0.28 ml, 1.56 mmol). The resulting mixture wasstirred at room temperature for 3 days. The reaction mixture was dilutedby DCM (30 mL) and the solution was washed with water (20 mL) and brine(20 mL). Organic layer was dried by MgSO₄ and concentrated under vacuo.The residue was purified by ISCO to give a glasslike solid. The solidwas further purified by being stirred in acetonitrile (2 mL) and diethylether (30 mL) to give3-(1-Oxo-4-{4-[4-(2,2,2-trifluoro-ethanesulfonyl)-piperazin-1-ylmethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (277 mg, 59% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75, (CH₃CN/0.1% H₃PO₄), 3.10 min(99.2%); 213-215° C. (in house); ¹H NMR (DMSO-d₆) δ 1.91-2.05 (m, 1H,CHH), 2.45 (d, J=8.7 Hz, 5H, CH₂, CH₂, CHH), 2.53-2.63 (m, 1H, CHH),2.83-2.99 (m, 1H, CHH), 3.17-3.27 (m, 4H, CH₂, CH₂), 3.53 (s, 2H, CH₂),4.25 (d, J=17.4 Hz, 1H, CHH), 4.36-4.58 (m, 3H, CH₂, CHH), 5.11 (dd,J=5.0, 13.1 Hz, 1H, CHH), 5.23 (s, 2H, CH₂), 7.33 (d, J=7.6 Hz, 4H, Ar),7.39-7.53 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.34,31.18, 45.06, 45.15, 50.02 (q, J=29.2 Hz, CF₃), 51.56, 51.81, 61.10,69.36, 114.97, 115.22, 123.22 (q, J=275.2 Hz, CF₃), 127.67, 128.91,129.80, 129.93, 133.30, 135.43, 137.57, 153.48, 167.97, 170.96, 172.81;LCMS MH=595; Anal. Calcd for C₂₇H₂₉F3N₄O₆S+0.5H₂O: C, 53.73; H, 5.01; N,9.28; Found: C, 53.67; H, 5.03; N, 9.17.

5.276 3-(4-{4-[4-(4-FLUORO-BENZENESULFONYL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the stirred solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(330 mg, 0.7 mmol) in DCM (10 mL) was added 1-(4-fluorophenylsulfonyl)piperazine (236 mg, 0.97 mmol) and DIPEA (0.26 mL, 1.5mmol). The resulting solution was stirred at room temperature for 20 hrsand then were added DCM (20 mL) and water (20 mL). The mixture wasextracted and the organic layer was washed with brine (20 mL). Organiclayer was dried by MgSO₄ and concentrated under vacuo. The residue waspurified by ISCO to give a white solid. The solid was further purifiedby being stirred in acetonitrile and diethyl ether to give3-(4-{4-[4-(4-Fluoro-benzenesulfonyl)-piperazin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (245 mg, 54% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75, (CH₃CN/0.1% H₃PO₄), 4.70 min(98.9%); mp: 192-194° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.04 (m, 1H, CHH),2.34-2.47 (m, 5H, CH₂, CH₂, CHH), 2.53-2.63 (m, 1H, CHH), 2.82-3.01 (m,5H, CHH, CH₂, CH₂), 3.47 (s, 2H, CH₂), 4.24 (d, J=17.6 Hz, H, CHH), 4.40(d, J=17.6 Hz, 1H, CHH), 5.08 (dd, J=4.9, 8.1 Hz, 1H, CHH), 5.21 (s, 2H,CH₂), 7.25 (d, 2H, Ar), 7.29-7.34 (m, 2H, Ar), 7.40 (d, J=7.9 Hz, 2H,Ar), 7.44-7.56 (m, 3H, Ar), 7.73-7.87 (m, 2H, Ar), 10.96 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 45.04, 45.90, 51.33, 51.53, 60.95,69.31, 114.93, 115.20, 116.60 (d, J=23.25 Hz, Ar), 127.63, 128.79,129.78, 129.90, 130.60 (d, J=9.75 Hz, Ar), 131.17, 133.27, 135.34,137.51, 153.45, 162.62 (d, J=249.75 Hz, Ar), 167.97, 170.96, 172.81;LCMS MH=607; Anal. Calcd for C₃₁H₃₁FN₄O₆S+.6H₂O:C, 60.30; H, 5.26; N,9.07; Found: C, 60.18; H, 5.18; N, 9.09.

5.2773-(4-{4-[4-(3,4-DIFLUORO-BENZENESULFONYL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To the stirred mixture of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(350 mg, 0.79 mmol) and 1-(3,4-difluorophenylsulfonyl) piperazine (269mg, 1.0 mmol) in DCM (10 mL) was added DIPEA (0.25 ml, 1.6 mmol). Theresulting mixture was stirred at room temperature for 3 days. Thereaction mixture was diluted by DCM (30 mL) and the solution was washedwith water (20 mL), brine (2×20 mL). Organic layer was dired by MgSO₄and filtered. The filtrate was concentrated under vacuo. And the residuewas purified by ISCO to give a white solid. The solid was furtherpurified by being stirred in acetonitrile and diethyl ether to give3-(4-{4-[4-(3,4-Difluoro-benzenesulfonyl)-piperazin-1-ylmethyl]-benzyloxy}-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (296 mg, 60% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 25/75, (CH₃CN/0.1% H₃PO₄), 6.70 min(99.9%); mp: 225-227° C.; ¹H NMR (DMSO-d₆) δ 1.91-2.04 (m, 1H, CHH),2.35-2.47 (m, 5H, CHH, CH₂, CH₂), 2.53-2.63 (m, 1H, CHH), 2.82-3.02 (m,5H, CHH, CH₂, CH₂), 3.48 (s, 2H, CH₂), 4.24 (d, J=17.4 Hz, 1H, CHH),4.40 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CHH), 5.21(s, 2H, CH₂), 7.26 (d, J=7.9 Hz, 2H, Ar), 7.30 (d, J=3.0 Hz, 1H, Ar),7.33 (d, J=2.1 Hz, 1H, Ar), 7.41 (d, J=8.1 Hz, 2H, Ar), 7.48 (t, J=7.7Hz, 1H, Ar), 7.62 (dd, J=2.0, 4.1 Hz, 1H, Ar), 7.73 (dd, J=7.7, 10.2 Hz,1H, Ar), 7.84 (ddd, J=2.1, 7.5, 9.7 Hz, 1H, Ar), 10.97 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 22.34, 31.16, 45.03, 45.90, 51.30, 51.53, 60.92, 69.31,114.93, 115.20, 17.45 (d, J=19.5, CF), 118.84 (d, J=17.2, CF), 125.43,127.63, 128.81, 129.78, 129.90, 132.11, 133.28, 135.35-137.50, 149.25(dd, J=228.0 Hz, J=12.0 Hz), 152.60 (dd, J=230.2 Hz, J=13.5 Hz), 153.43,167.97, 170.96, 172.83; LCMS MH=625; Anal. Calcd for C₃₁H₃₀F2N₄O₆S: C,59.61; H, 4.84; N, 8.97; Found: C, 59.34; H, 4.72; N, 8.88.

5.278(S)-3-(1-OXO-4-((4-((4-(TRIFLUOROMETHYL)PIPERIDIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a suspension of(S)-3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(1 g, 2.256 mmol) in MeCN (20 mL) at 0° C., was added4-(trifluoromethyl)piperidine hydrochloride (0.470 g, 2.481 mmol). DIEA(0.788 mL, 4.51 mmol) was immediately added and the resulting mixturewas stirred at 0° C. for 3 h. Tetrabutylammonium bromide (0.036 g, 0.113mmol) was added to the reaction mixture and stirring was continued for 1h at 0° C. then at room temperature for ˜18 h. The reaction slurry wasconcentrated to dryness under vacuum to give ˜1.2 g of a yellow solid.This solid was partitioned between EtOAc (˜250 mL) and aq 1N NaHCO₃(˜100 mL). The organic layer was washed with another 100 mL of 1NNaHCO₃, water (˜25 mL), and Brine (˜50 mL). The solution was dried overNa₂SO₄, filtered, and concentrated on rotovap to a minimum volume ofEtOAc (˜5-7 mL) at 40° C. to first sign of cloudiness. The flask wasremoved from rotovap and allowed to stand at room temperature. Moresolids formed upon standing.

An equal volume of MTBE (5-7 mL) was added to the slurry. The mixturewas swirled and then filtered on 30-mL fine fritted funnel with suction.Additional MTBE was used to wash the cake and transfer residual solidfrom flask (˜25 mL). The cake was suction dried and then placed invacuum oven overnight at 50° C. to give 850 mg (73% yield) of a white tolight cream colored solid. To remove unwanted residual solvents (EtOAcand MTBE), a second recrystallization was carried out from warmMeCN/water. The solid was collected on a fine fritted funnel, washedwith water (˜25 mL), and the cake was dried in a vacuum oven at 60° C.overnight to give(S)-3-(1-oxo-4-((4-((4-(trifluoromethyl)piperidin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dioneas a white solid (485 mg, 61% recovery): HPLC:Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 6.33 min (99.0%);Chiral HPLC: Chiral Technologies, AGP analytical column, 99% ee bycomparison with a racemic sample previously synthesized; mp: 158-160; ¹HNMR (DMSO-d₆) δ 1.33-1.56 (m, 2H, CHH, CHH), 1.67-1.84 (m, 2H, CHH,CHH), 1.86-2.09 (m, 3H, CHH, CH₂), 2.14-2.34 (m, 1H, CH), 2.35-2.48 (m,1H, CHH), 2.53-2.64 (m, 1H, CHH), 2.78-3.00 (m, 3H, CH₂, CHH), 3.48 (br.s., 2H, CH₂), 4.25 (d, J=17.4 Hz, 1H, CHH), 4.42 (d, J=17.6 Hz, 1H,CHH), 5.11 (dd, J=5.0, 13.3 Hz, 1H, CH), 5.23 (s, 2H, CH₂), 7.25-7.39(m, 4H, Ar), 7.40-7.55 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆)δ 22.34, 24.21, 31.18, 45.06, 51.37, 51.56, 61.59, 69.38, 114.96,115.22, 127.72 (q, J=280.6 Hz, CF₃), 127.64, 128.81, 129.78, 129.93,133.30, 135.22, 138.12, 153.48, 167.97, 170.95, 172.80. CF₃ C isoverlapped with DMSO and not observed; LCMS: MH=516; Anal Calcd forC₂₇H₂₈F3N₃O₄+0.5H₂O: C, 61.83; H, 5.57; N, 8.01; F, 10.87; Found: C,61.81; H, 5.40; N, 8.06; F, 10.51.

5.2793-{1-OXO-4-[4-(4-PYRIDIN-2-YL-PIPERAZIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To a suspension3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300 mg, 0.677 mmol) in dry MeCN (10 mL), was added1-(pyridin-2-yl)piperazine (116 mg, 0.711 mmol) followed by DIEA (0.236mL, 1.354 mmol). The resulting mixture was stirred at room temperaturefor 16 h. The thick slurry was then warmed to 50° C., resulting in aclear yellow solution. After ˜7 h at 50° C., the heat was removed andthe solution was stirred gently for about 1 h and then allowed to standat room temperature overnight. The resulting slurry was gently agitatedand then filtered on a 30-mL medium fritted funnel with suction. Theresidual solid remaining in reaction vial was transferred onto funnelwith additional MeCN (˜2 mL). The cake was washed with several portionsof Et₂O (total volume ˜70 mL) and then slurried in water and thensuctioned dried. The solid was washed with small portions of water(total volume ˜50 mL). The remaining white solid was reslurried in wateron funnel and then suctioned dried. The solid was washed with additionalwater (total volume ˜50 mL) and then placed in vacuum oven at 60° C.overnight to give3-{1-oxo-4-[4-(4-pyridin-2-yl-piperazin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (260 mg, 73% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 13/87 CH₃CN/0.1% H₃PO₄, 5.11 min (99.2%);mp: 165-167° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.07 (m, 1H, CHH), 2.34-2.49(m, 5H, CHH, CH₂, CH₂), 2.57 (d, J=18.7 Hz, 1H, CHH), 2.81-3.03 (m, 1H,CHH), 3.38-3.51 (m, 4H, CH₂, CH₂), 3.53 (br. s., 2H, CH₂), 4.26 (d,J=17.4 Hz, 1H, CHH), 4.43 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.1Hz, 1H, CH), 5.24 (s, 2H, CH₂), 6.63 (dd, J=5.1, 6.8 Hz, 1H, Ar), 6.79(d, J=8.7 Hz, 1H, Ar), 7.25-7.42 (m, 4H, Ar), 7.42-7.66 (m, 4H, Ar),8.09 (dd, J=1.4, 4.8 Hz, 1H, Pyr), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆)δ 22.34, 31.18, 44.53, 45.07, 51.55, 52.29, 61.69, 69.36, 107.01,112.94, 114.96, 115.22, 127.66, 129.03, 129.80, 129.93, 133.30, 135.33,137.44, 137.86, 147.49, 153.48, 158.95, 167.99, 170.96, 172.83; LCMS:MH=526; Anal Calcd for C₃₀H₃₁N₅O_(4+1.2)H₂O: C, 65.87; H, 6.15; N,12.80; Found: C, 65.87; H, 5.93; N, 12.68.

5.2803-(1-OXO-4-{4-[4-(5-TRIFLUOROMETHYL-[1,3,4]-THIADIAZOL-2-YL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE

To a suspension of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300 mg, 0.677 mmol) in dry MeCN (10 mL), was added2-(piperazin-1-yl)-5-(trifluoromethyl)-1,3,4-thiadiazole (169 mg, 0.711mmol) followed by DIEA (0.236 mL, 1.354 mmol). The resulting mixture wasstirred at room temperature for 16 h. The mixture was heated to 50° C.for 8 h and then to 80° C. for 1 h. The reaction mixture was allowed tostand overnight at room temperature then swirled gently to resuspendsolids at bottom of vial. The solid was collected on a 30-mL mediumfritted funnel with suction. Residual solid in the vial was transferredonto funnel with additional MeCN (˜1 mL). The white cake was washed withseveral portions of Et₂O (total volume ˜30 mL). The remaining whitesolid was reslurried in water on funnel and then suctioned dried. Thesolid was washed with additional water (total volume ˜50 mL) and thenplaced in vacuum oven at 60° C. overnight to give3-(1-oxo-4-{4-[4-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazin-1-ylmethyl]-benzyloxy}-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dioneas a white solid (332 mg, 82% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 22/78 CH₃CN/0.1% H₃PO₄, 7.89 min (99.9%);mp: 160-162° C.; ¹H NMR (DMSO-d₆) δ 1.90-2.08 (m, 1H, CHH), 2.36-2.47(m, 1H, CHH), 2.50-2.63 (m, 5H, CHH, pip CH₂, CH₂), 2.82-3.04 (m, 1H,CHH), 3.44-3.70 (m, 6H, CH₂, pip CH₂, CH₂), 4.26 (d, J=17.6 Hz, 1H,CHH), 4.42 (d, J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CH),5.24 (s, 2H, CH₂), 7.35 (t, J=8.3 Hz, 4H, Ar), 7.43-7.54 (m, 3H, Ar),10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.34, 31.18, 45.06, 49.58,51.27, 51.55, 61.29, 69.35, 114.97, 115.23, 121.36, 127.69, 129.00,129.80, 129.95, 133.30, 135.47, 137.48, 153.48, 167.99, 170.96, 172.81,173.95. One carbon signal is missing, possibly CF₃ due to splitting;LCMS: MH=601; Anal Calcd for C₂₈H₂₇F3N₆O₄S+0.9H₂O: C, 54.52; H, 4.71; N,13.62; F, 9.24; Found: C, 54.50; H, 4.57; N, 13.52; F, 9.24.

5.2813-(4-((4-((4-(2-METHYL-6-(TRIFLUOROMETHYL)PYRIMIDIN-4-YL)PIPERAZIN-1-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To a suspension of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300 mg, 0.677 mmol) in dry MeCN (10 mL), was added2-methyl-4-(piperazin-1-yl)-6-(trifluoromethyl)pyrimidine (175 mg, 0.711mmol) followed by DIEA (0.236 mL, 1.354 mmol). The resulting mixture wasstirred at room temperature for 16 h. The mixture was heated to 50° C.until it became a clear solution and was then allowed to cool to roomtemperature with gentle stirring overnight. A white solid formed uponstanding. The mixture was agitated and the solid was collected on a15-mL fine fritted funnel with suction. The solid was washed withminimal MeCN (˜1 mL) and several portions of Et₂O (total volume ˜35 mL).The white solid was suction dried and then placed in a vacuum oven at60° C. overnight to give3-(4-((4-((4-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (276 mg, 67% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 22/78 CH₃CN/0.1% H₃PO₄, 7.59 min (99.7%);mp: 165-167° C.; ¹H NMR (DMSO-d₆) δ 1.89-2.07 (m, 1H, CHH), 2.38-2.48(m, 8H, CH₂, CH₂, CHH. CH₃), 2.53-2.65 (m, 1H, CHH), 2.79-2.99 (m, 1H,CHH), 3.53 (s, 2H, CH₂), 3.59-3.91 (m, 4H, CH₂, CH₂), 4.26 (d, J=17.4Hz, 1H, CHH), 4.43 (d, J=17.6 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz,1H, CH), 5.24 (s, 2H, CH₂), 7.05 (s, 1H, Pyr), 7.28-7.40 (m, 4H, Ar),7.42-7.55 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.34,25.65, 31.18, 43.53, 45.07, 51.56, 52.06, 61.43, 69.38, 96.73 (q, J=3.3Hz, CCCF₃), 114.97, 115.22, 121.18 (q, J=275.1 Hz, CF₃), 127.66, 128.97,129.78, 129.95, 133.30, 135.38, 137.66, 153.26 (q, J=34.1 Hz, CCF₃),153.49, 161.75, 167.64, 167.99, 170.96, 172.81. CF₃ quartet at 121.18ppm is observed as a doublet (outer signals are missing); LCMS: MH=609;Anal Calcd for C₃₁H₃₁F3N₆O₄+0.4H₂O: C, 60.46; H, 5.20; N, 13.65; F,9.25; Found: C, 60.51; H, 5.13; N, 13.61; F, 8.97.

5.2823-{1-OXO-4-[4-(4-PHENOXY-PIPERIDIN-1-YLMETHYL)-BENZYLOXY]-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To a 20-mL reaction vial charged with3-(4-((4-(bromomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(300 mg, 0.677 mmol) and 4-phenoxypiperidine (126 mg, 0.711 mmol), wasadded dry MeCN (10 mL) followed by DIEA (0.236 mL, 1.35 mmol). Theresulting suspension was warmed to 50° C. to give a clear solution.After ˜30 min, the temperature was raised further to 70° C. and thereaction mixture was stirred for ˜16 h at 70° C. The mixture was allowedto cool to room temperature and then placed at 4° C. overnight forming awhite solid. The slurry was gently agitated and the solid was collectedon a 15-mL medium fritted funnel with suction. The cake was washed withEt₂O (˜50 mL) and suction dried to give a tan solid. The solid wastriturated and washed with water (˜50 mL), suction dried, and then driedfurther in a vacuum oven at 50° C. to give3-{1-oxo-4-[4-(4-phenoxy-piperidin-1-ylmethyl)-benzyloxy]-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a light tan solid (254 mg, 70% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 ml/min, 240 nm, 27/73 CH₃CN/0.1% H₃PO₄, 4.54 min(99.0%); mp: 180-182° C.; ¹H NMR (DMSO-d₆) δ 1.49-1.71 (m, 2H, CH₂),1.82-2.07 (m, 3H, CHH, CH₂), 2.15-2.31 (m, 2H, CH₂), 2.36-2.49 (m, 1H,CHH), 2.52-2.62 (m, 1H, CHH), 2.63-2.75 (m, 2H, CH₂), 2.81-3.00 (m, 1H,CHH), 3.49 (s, 2H, CH₂), 4.25 (d, J=17.4 Hz, 1H, CHH), 4.32-4.49 (m, 2H,CHH, CHO), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.23 (s, 2H, CH₂),6.78-7.04 (m, 3H, Ar), 7.19-7.30 (m, 2H, Ar), 7.33 (dd, J=1.7, 7.7 Hz,4H, Ar), 7.42-7.62 (m, 3H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ22.33, 30.62, 31.16, 45.07, 50.10, 51.55, 61.64, 69.41, 72.13, 114.96,115.20, 115.76, 120.42, 127.61, 128.81, 129.46, 129.78, 129.93, 133.28,135.15, 138.40, 153.49, 157.04, 167.97, 170.95, 172.80; LCMS: MH=540;Anal Calcd for C₃₂H₃₃N₃O₅+0.5H₂O: C, 70.06; H, 6.25; N, 7.66; Found: C,70.11; H, 5.97; N, 7.62.

5.2832-(2,6-DIOXO-PIPERIDIN-3-YL)-4-{4-[4-(4-FLUORO-PHENYL)-PIPERIDIN-1-YLMETHYL]-BENZYLOXY}-ISOINDOLE-1,3-DIONE

To the CH₂Cl₂ suspension of2-(2,6-dioxopiperidin-3-yl)-4-(4-((4-(4-fluorophenyl)piperidin-1-yl)methyl)benzyloxy)isoindoline-1,3-dione(170 mg, 0.306 mmol, 56.0% yield) was added 4-(4-fluorophenyl)piperidinehydrochloride (130 mg, 0.601 mmol) and N-ethyl-N-isopropylpropan-2-amine(0.292 ml, 1.640 mmol). The mixture was stirred at room temperatureovernight. The mixture was added CH₂Cl₂ and water and extracted. Theorganic layer was concentrated. The resulted solid was stirred in CH₂Cl₂(5 mL) and the suspension was filtered to give a white solid (170 mg,56%). Melting point: 155-157° C. LC-MS m/e=556. HPLC Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, isocratic 25/75 CH₃CN/0.1%H₃PO₄ in H₂O:t_(R)=4.06 min (98.5%); ¹H NMR (DMSO-d₆) δ 1.53-1.76 (m,4H, CH₂, CH₂), 2.03 (t, J=11.3 Hz, 3H, CHH, CH₂), 2.41-2.46 (m, 1H,CHH), 2.54-2.65 (m, 2H, CHH. CH), 2.80-2.99 (m, 4H, CHH, CH₂), 3.50 (s,2H, CH₂), 5.09 (dd, J=4.2, 13.4 Hz, 1H, CNH), 5.35 (s, 2H, CH₂),7.03-7.16 (m, 2H, Ar), 7.22-7.31 (m, 2H, Ar), 7.32-7.40 (m, 2H, Ar),7.43-7.50 (m, 3H, Ar), 7.54-7.68 (m, 1H, Ar), 7.81 (d, J=7.2 Hz, 1H,Ar), 11.10 (br. s., 1H, NH). ¹³C NMR (DMSO-d₆) δ 21.95, 30.90, 33.13,38.66, 41.00, 48.73, 53.51, 62.06, 69.99, 114.71, 114.99, 115.48,116.58, 120.19, 127.23, 128.33, 128.43, 128.92, 133.26, 134.63, 136.97,138.42, 142.34, 155.53, 158.96, 162.17, 165.27, 166.75, 169.85, 172.71;Anal Calcd for C₃₂H₃₀FN₃O₅+0.6 CH₂Cl₂: C: 64.55%; H: 5.10%; N: 6.93%;Found: C: 64.49%; H: 4.89%; N: 7.03%.

5.2842-(2,6-DIOXO-PIPERIDIN-3-YL)-4-{4-[4-(2,2,2-TRIFLUORO-ETHYL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-ISOINDOLE-1,3-DIONE

To the CH₂Cl₂ solution of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(250 mg, 0.547 mmol) was added 1-(2,2,2-trifluoroethyl)piperazinehydrochloride (123 mg, 0.601 mmol) and N-ethyl-N-isopropylpropan-2-amine(292 μl, 1.640 mmol). The mixture was stirred at room temperatureovernight. The reaction mixture was added CH₂Cl₂ (15 mL) and water (10mL). and extracted. The organic layer was concentrated and purified onsilica gel column eluted with MeOH and CH₂Cl₂ to give2-(2,6-dioxo-piperidin-3-yl)-4-{4-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-ylmethyl]-benzyloxy}-isoindole-1,3-dioneas a white solid (170 mg, 57%). Melting point: 163-165° C. LC-MSm/e=545. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, mL/min, 240 nm,isocratic 25/75 CH₃CN/0.1% H₃PO₄ in H₂O:t_(R)=5.40 min (99%); ¹H NMR(DMSO-d₆) δ 1.96-2.10 (m, 1H, CHH), 2.37 (br. s., 4H, CH₂, CH₂),2.43-2.47 (m, OH, CHH), 2.52-2.66 (m, J=4.5 Hz, 6H, CH₂, CH₂, CH₂, CH),2.79-2.97 (m, 1H, CHH), 3.14 (d, J=10.2 Hz, 2H, CH₂), 3.46 (s, 2H, CH₂),5.09 (dd, J=5.4, 12.7 Hz, 1H, NCH), 5.35 (s, 2H, CH₂), 7.33 (d, J=8.1Hz, 2H, Ar), 7.46 (dd, J=4.1, 7.6 Hz, 3H, Ar), 7.60 (d, J=8.5 Hz, 1H,Ar), 7.83 (dd, J=7.4, 8.5 Hz, 1H, Ar), 11.11 (s, 1H, NH). ¹³C NMR(DMSO-d₆) δ 21.93, 30.90, 48.73, 52.45, 53.06, 56.23, 56.62, 57.39,57.01, 61.58, 69.95, 115.48, 116.58, 120.19, 127.23, 127.80, 128.87,133.26, 134.71, 136.96, 137.98, 155.52, 165.27, 166.75, 169.85, 172.71.Anal Calcd for C₂₇H₂₇F3N₄O₅, C: 59.56%; H: 5.00%; N: 10.29%; Found: C:59.44%; H: 4.87%; N: 10.23%. 5.2853-(4-((4-((4-(2,4-DIFLUOROPHENYL)PIPERAZIN-1-YL)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

To the CH₂Cl₂ solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.5 g, 1.128 mmol) was added 1-(2,4-difluorophenyl)piperazine (0.235 g,1.184 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.602 ml, 3.38 mmol).The mixture was stirred at room temperature overnight. The reactionmixture was added water (15 mL), extracted and concentrated to give ayellowish solid. The solid was recrystallized from CH₃CN (10 mL) to give3-(4-((4-((4-(2,4-difluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (330 mg, 52%). Melting point (determined in house):207-209° C. LC-MS m/e=561. HPLC Waters Symmetry C-18, 3.9×150 mm, 5micro, 1 mL/min, 240 nm, isocratic 25/75 CH₃CN/0.1% H₃PO₄ in H₂O: 6.80min (98.8%). ¹H NMR (DMSO-d₆) δ 1.90-2.06 (m, 1H, CHH), 2.36-2.45 (m,J=4.2 Hz, 1H, CHH), 2.53-2.59 (m, 5H, CHH, CH₂, CH₂), 2.83-3.01 (m, 5H,CH₂, CH₂, CHH), 3.54 (s, 2H, CH₂), 4.05-4.58 (m, 2H, CH₂), 5.11 (dd,J=5.0, 13.1 Hz, 1H, NCH), 5.24 (s, 2H, CH₂), 6.89-7.12 (m, 2H, Ar), 7.17(ddd, J=2.8, 9.2, 12.4 Hz, 1H, Ar), 7.27-7.41 (m, 4H, Ar), 7.41-7.51 (m,3H, Ar), 10.97 (s, 1H, Ar). ¹³C NMR (DMSO-d₆) δ 22.33, 31.16, 45.07,50.44, 51.55, 52.52, 61.64, 69.39, 104.18, 104.52, 104.87, 110.80,111.03, 114.96, 115.22, 119.86, 119.91, 127.63, 128.98, 129.80, 129.95,133.30, 135.28, 137.88, 153.49, 167.99, 170.95, 172.80. Anal Calcd forC₃₁H₃₀F2N₄O₄: C %: 66.42, H %: 5.39, N %: 9.99; Found: C %: 65.08, H %:5.02, N %: 9.66.

5.2864-((4-((4-(2,4-DIFLUOROPHENYL)PIPERIDIN-1-YL)METHYL)BENZYL)OXY)-2-(2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE

To the CH₂Cl₂ suspension of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(0.5 g, 1.093 mmol) was added 4-(2,4-difluorophenyl)piperidine (0.216 g,1.093 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.584 ml, 3.28 mmol).The suspension was stirred at room temperature overnight. The mixturewas added water (10 mL), CH₂Cl₂ (10 mL), extracted and concentrated. Theresulted oil was purified on silica gel column eluted with MeOH andCH₂Cl₂ to give a solid which was stirred with CH₂Cl₂ (3 mL) and filteredto give4-((4-((4-(2,4-difluorophenyl)piperidin-1-yl)methyl)benzyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneas white solid (50 mg, 8%). Melting point: 153-155° C. LC-MS m/e⁼574.HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm,isocratic 30/70 CH₃CN/0.1% H₃PO₄ in H₂O: 4.69 min (97.6%). ¹H NMR(DMSO-d₆) δ 1.55-1.75 (m, 4H, CH₂, CH₂), 2.05 (d, J=2.1 Hz, 3H, CH₂,CHH), 2.43-2.48 (m, 1H, CHH), 2.55-2.67 (m, 2H, CHH), 2.68-2.86 (m, 2H,CHH, CH), 2.82-2.82 (m, OH, M₀₁), 2.86-2.99 (m, 3H, CHH, CH₂), 3.51 (s,2H, CH₂), 4.89-5.18 (m, 1H, NCH), 5.36 (s, 2H, CH₂), 6.91-7.08 (m, 1H,Ar), 7.09-7.23 (m, 1H, Ar), 7.27-7.54 (m, 7H, Ar), 7.61 (d, J=8.3 Hz,1H, Ar), 7.74-7.95 (m, 1H, Ar), 11.10 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ21.93, 30.90, 31.63, 34.63, 48.73, 53.47, 62.01, 69.98, 103.20, 103.57,103.90, 115.48, 116.58, 120.21, 127.25, 128.91, 129.09, 133.26, 134.65,136.97, 138.40, 138.53, 155.53, 165.29, 166.75, 169.87, 172.71.

5.2874-((4-((4-(4-CHLOROPHENYL)PIPERIDIN-1-YL)METHYL)BENZYL)OXY)-2-(2,6-DIOXOPIPERIDIN-3-YL)ISOINDOLINE-1,3-DIONE

To the CH₂Cl₂ suspension of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(0.35 g, 0.765 mmol) was added 4-(4-chlorophenyl)piperidine (0.157 g,0.804 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.409 ml, 2.296mmol). The suspension was stirred at room temperature overnight. Thereaction mixture was loaded on the silica gel column and eluted withMeOH and CH₂Cl₂ to give4-((4-((4-(4-chlorophenyl)piperidin-1-yl)methyl)benzyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneas a white solid (320 mg, 73%). Melting point: 236-238° C. LC-MSm/e⁼572, 574. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min,240 nm, isocratic 30/70 CH₃CN/0.1% H₃PO₄ in H₂O: 6.17 min (98.4%). ¹HNMR (DMSO-d₆) 1.50-1.79 (m, 4H, CH₂, CH₂), 1.96-2.11 (m, 3H, CHH, CH₂),2.46-2.66 (m, 3H, CH, CHH, CHH), 2.79-2.99 (m, 3H, CH₂, CHH), 3.50 (s,2H, CH₂), 5.09 (dd, J=5.4, 12.7 Hz, 1H, NCH), 5.36 (s, 2H, CH₂),7.19-7.40 (m, 6H, Ar), 7.42-7.52 (m, 3H, Ar), 7.61 (d, J=8.5 Hz, 1H,Ar), 7.74-7.96 (m, 1H, Ar), 11.11 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ21.95, 30.90, 32.88, 41.11, 48.73, 53.44, 62.03, 69.98, 115.48, 116.58,120.19, 127.23, 128.15, 128.57, 128.91, 130.40, 133.26, 134.63, 136.97,138.40, 145.21, 155.53, 165.27, 166.75, 169.85, 172.70. Anal Calcd forC₃₂H₃₀ClN₃O₅: C %: 67.19; H %: 5.29; N %: 7.35; Found: C %: 66.83; H %:5.31; N %: 7.13.

5.2882-(2,6-DIOXOPIPERIDIN-3-YL)-4-((4-((4-((TRIFLUOROMETHYL)SULFONYL)PIPERAZIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLINE-1,3-DIONE

To the CH₂Cl₂ solution of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(0.25 g, 0.547 mmol) was added 1-(trifluoromethylsulfonyl)piperazine(0.143 g, 0.656 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.212 g,1.640 mmol). The suspension was stirred at room temperature overnight.The mixture was added water (15 mL), CH₂Cl₂ (20 mL), extracted,concentrated and the resulted oil was purified on silica gel column togive a solid. The solid was purified on prep-HPLC to give2-(2,6-dioxopiperidin-3-yl)-4-((4-((4-((trifluoromethyl)sulfonyl)piperazin-1-yl)methyl)benzyl)oxy)isoindoline-1,3-dionesolid (80 mg, 25%). Melting point: 229-231° C. LC-MS m/e=595. HPLCWaters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, isocratic30/70 CH₃CN/0.1% H₃PO₄ in H₂O: 3.79 (97%). ¹H NMR (DMSO-d₆) δ 1.94-2.12(m, 1H, CHH), 2.35-2.45 (m, 1H, CHH), 2.53-2.67 (m, 5H, CHH, CH₂, CH₂),2.80-2.98 (m, 1H, CHH), 3.48 (br. s., 4H, CH₂, CH₂), 3.56 (s, 2H, CH₂),5.09 (dd, J=5.4, 12.7 Hz, 1H, NCH), 5.35 (s, 2H, CH₂), 7.27-7.42 (m, 2H,Ar), 7.48 (d, J=6.8 Hz, 3H, Ar), 7.60 (d, J=8.5 Hz, 1H, Ar), 7.83 (dd,J=7.4, 8.3 Hz, 1H, Ar), 11.11 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 21.95,30.89, 46.38, 48.73, 51.87, 61.01, 69.90, 115.50, 120.18, 127.35,128.97, 133.26, 133.75, 134.99, 136.97, 137.34, 155.50, 165.29, 166.79,169.85, 172.71. Anal Calcd for C₂₆H₂₅F3N₄O₇S+1.1H₂O: C %: 51.17; H %:4.30; N %: 9.12; Found: C %: 50.83; H %: 4.46; N %: 8.74.

5.2892-(2,6-DIOXO-PIPERIDIN-3-YL)-4-{4-[4-(4-FLUORO-PHENYL)-PIPERAZIN-1-YLMETHYL]-BENZYLOXY}-ISOINDOLE-1,3-DIONE

To the CH₂Cl₂ suspension of4-(4-(bromomethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(0.25 g, 0.547 mmol) was added 1-(4-fluorophenyl)piperazine (0.108 g,0.601 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.212 g, 1.640 mmol).The mixture was stirred at room temperature overnight. The reactionmixture was added water (10 mL) and CH₂Cl₂ (15 mL) and extracted. Theorganic layer was concentrated then purified on silica gel column elutedwith CHCl₂ and MeOH to give2-(2,6-dioxo-piperidin-3-yl)-4-{4-[4-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-benzyloxy}-isoindole-1,3-dioneas yellowish solid (0.24 g, 79%). Melting point: 135-137° C. LC-MSm/e=557. HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240nm, isocratic 25/75 CH₃CN/0.1% H₃PO₄ in H₂O:t_(R)=7.07 min (99%); ¹H NMR(DMSO-d₆) δ 1.92-2.13 (m, 1H, CHH), 2.41-2.47 (m, 1H, CHH), 2.54-2.67(m, 5H, CHH, CH₂, CH₂), 2.79-2.97 (m, 1H, CHH), 2.98-3.19 (m, 4H, CH₂,CH₂), 3.53 (s, 2H, CH₂), 5.09 (dd, J=5.4, 12.7 Hz, 1H, NCH), 5.36 (s,2H, CH₂), 6.80-6.97 (m, 2H, Ar), 6.97-7.15 (m, 2H, Ar), 7.29-7.41 (m,2H, Ar), 7.42-7.55 (m, 3H, Ar), 7.61 (d, J=8.5 Hz, 1H, Ar), 7.83 (dd,J=7.4, 8.5 Hz, 1H, Ar), 11.11 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 21.95,30.90, 48.75, 48.97, 52.51, 61.65, 69.96, 115.03, 115.31, 115.50,116.98, 117.09, 120.21, 127.28, 129.00, 133.26, 134.79, 136.97, 137.94,147.92, 154.35, 155.53, 157.47, 165.29, 166.75, 169.87, 172.71; AnalCalcd for C₃₁H₂₉FN₄O₅+0.2H₂O: C: 66.47%; H: 5.29%; N: 10.00%; Found: C:66.16%; H: 5.17%; N: 9.93%.

5.2903-(4-BENZO[D]THIAZOL-2-YLOXY-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Cesium carbonate (4.6 g, 14.1 mmol) was added to a stirredsolution of methyl 3-hydroxy-2-methylbenzoate (2.0 g, 12.0 mmol) and2-chlorobenzothiazole (3.1 g, 18.1 mmol) in acetonitrile (50 mL). Theresulting mixture was stirred at room temperature overnight. Thereaction mixture was filtered and washed with acetonitrile (25 mL), thefiltrate was concentrated, and the residue was purified bychromatography (SiO₂, EtOAc: Hexane 1: 9) to give methyl3-(benzo[d]thiazol-2-yloxy)-2-methylbenzoate (3.4 g, 93% yield): ¹H NMR(CDCl₃) δ 2.52 (s, 3H, CH₃), 3.92 (s, 3H, OCH₃), 7.23-7.43 (m, 4H, Ar),7.63-7.75 (m, 2H, Ar), 7.86 (dd, J=1.2 and 7.8 Hz, 1H, Ar).

Step 2: N-Bromosuccinimide (2.2 g, 12.1 mmol) was added to a stirredsolution of methyl 3-(benzo[d]thiazol-2-yloxy)-2-methylbenzoate (3.3 g,11.0 mmol) in CCl₄ (70 mL). The resulting mixture was heated at 70° C.oil bath with a 300 W bulb shining on the reaction mixture for 2 hours.The reaction mixture was cooled and filtered. Filtrate was washed withwater (2×40 mL) and brine (40 mL), and dried. The solvent was removedand the residue was purified by chromatography (SiO₂, EtOAc: Hexane 1:9) to give methyl 3-(benzo[d]thiazol-2-yloxy)-2-(bromomethyl)benzoate(3.4 g, 8.1% yield): ¹H NMR (DMSO-d6) δ 3.92 (s, 3H, CH₃), 4.98 (s, 2H,CH₂), 7.21-7.50 (m, 2H, Ar), 7.56-7.76 (m, 2H), 7.79-7.93 (m, 2H, Ar),7.99 (d, J=7.2 Hz, 1H, Ar).

Step 3: Triethylamine (2.0 g, 19.8 mmol) was added to a stirredsuspension of methyl 3-(benzo[d]thiazol-2-yloxy)-2-(bromomethyl)benzoate(3.0 g, 7.9 mmol) and α-aminoglutarimide hydrochloride (1.3 g, 7.9 mmol)in acetonitrile (100 mL). After addition, the mixture was heated at 45°C. for 3 hours then heated to 85° C. overnight. The reaction mixture wascooled and concentrated. The residue was stirred with water (50 mL) togive a solid, which was reslurried with acetone (20 mL) to give a lightblue solid (1.5 g, 46%) of3-(4-benzo[d]thiazol-2-yloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.The color was removed by dissolving in acetone, treating withdecolorizing carbon, and filtering through Millpole (0.45 pM): mp258-260° C.; ¹H NMR (DMSO-d₆) δ 1.90-2.04 (m, 1H), 2.31-2.45 (m, 1H),2.57 (b, 1H), 2.78-2.99 (m, 1H), 4.33 (d, J=17.7 Hz, 1H), 4.48 (d,J=17.4 Hz, 1H), 5.12 (dd, Jz5.1 and 13.2 Hz, 1H), 7.30-7.49 (m, 2H),7.64-7.84 (m, 4H), 7.99 (d, J=7.2 Hz, 1H), 10.96 (s, 1H); ¹³C NMR(DMSO-d₆) δ 22.15, 31.07, 45.10, 51.66, 121.29, 121.43, 122.33, 124.42,124.44, 126.56, 130.40, 131.94, 133.22, 134.39, 148.20, 148.92, 167.03,170.52, 170.75, 172.73; Calcd. For C₂₀H₁₅N₃O₄S: C, 61.06: H, 3.84; N,10.68; S, 8.15. Found: C, 61.00; H, 3.72; N, 10.59; S, 8.20.

5.2913-[4-(4-METHYL-CYCLOHEXYLMETHOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Polymer-supported triphenylphosphene (1.6 mmol/g, 1.90 g, 2.36mmol) was added to a stirred solution of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.31 g, 1.07 mmol) in THF (20 mL) at 0° C., followed byaddition of diisopropyl diazene-1,2-dicarboxylate (0.27 ml, 2.14 mmol).After stirring for 30 minutes, (4-methyl-cyclohexyl)-methanol (cis &trans mixture, 0.41 g, 1.85 mmol) was added. The mixture was stirredovernight at room temperature then filtered, washed with methanol (3×10mL), then with methylene chloride (3×10 mL). The combined filtrate wasevaporated in vacuo to give an oil, which was purified on silica gelcolumn (MeOH/CH₂Cl₂ gradient from 0% to 9% in 60 min) to give4-carbamoyl-4-[4-(4-methyl-cyclohexylmethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester as a clear oil (0.35 g, 81% yield). ¹H NMR showed 61%to 39% ratio. It was used in the next step without further purification.

Step 2: Potassium tert-butoxide (0.10 g, 0.87 mmol) was added to astirred solution of4-carbamoyl-4-[4-(4-methyl-cyclohexylmethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.35 g, 0.87 mmol) in THF (10 mL) at 0° C. Themixture was stirred for ten minutes and quenched with 1N HCl (3 mL),neutralized by saturated sodium bicarbonate (4 mL to pH=7), and quicklyextracted by ethyl acetate (2×30 mL). The combined ethyl acetate phaseswere evaporated to an off-white solid, which was purified by preparativeHPLC (0.1% formic acid/water, and 0.1% formic acid/acetonitrile) to give3-[4-(4-methyl-cyclohexylmethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas an off-white solid (0.03 g, 10% yield); HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 40/60 in 10 min(acetonitrile/0.1% H₃PO₄), 4.68 min (60.2%), 5.07 min (37.3%); mp: N/Adue to limited sample available; ¹H NMR (DMSO-d₆) δ 0.78-2.08 (m, 15H,CH₃, 5CH₂, CH, CHH), 2.38-2.46 (m, 1H, CHH), 2.54-2.65 (m, 1H, CHH),2.80-3.01 (m, 1H, CHH), 3.87-4.08 (m, 2H, CH₂ (62% to 38%)), 4.15-4.46(m, 2H, ArCH₂), 5.11 (dd, 1H, NCH), 7.16-7.34 (m, 2H, Ar), 7.41-7.54 (m,1H, Ar), 10.97 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 19.94, 22.35, 22.57,24.87, 29.04, 29.39, 30.10, 31.20, 32.23, 34.10, 34.51, 36.82, 44.99,51.58, 70.85, 73.02, 114.43, 114.54, 114.84, 129.71, 129.84, 133.18,153.91, 168.08, 171.02, 172.85; LCMS MH=371.

5.2923-[4-(2-BENZOFURAN-2-YL-ETHOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the suspension of 2-iodo phenyl (0.22 g, 1 mmol) in water (3mL), was added s-prolinol (0.29 mL, 3 mmol) followed by Pd on carbon (70mg, 0.03 mmol), tripehenylphosphine (35 mg, 0.13 mmol), and cupperiodide (13 mg, 0.07 mmol). The mixture was stirred at room temperaturefor 1 hour. 3-Butyn-1-ol (0.23 mL, 3 mmol) was added and the mixture wasstirred at 80° C. for 3 hours. The mixture was cooled to roomtemperature and concentrated on rota-vap. The resulting mixture waspurified on silica gel column eluted with ethyl acetate and hexane(gradient, product came out at 6% methanol) to give2-benzofuran-2-yl-ethanol (0.1 g, 62%).

Step 2: To the THF solution (10 mL) of4-carbamoyl-4-(4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyric acidmethyl ester (0.54 g, 1.85 mmol), were added triphenyl phosphine resin(2.4 g, 1.5 mmol/g loading, 3.7 mmol) and DIAD (0.72 mL, 3.7 mmol) at 0°C. After being stirred at 0° C. for 10 minutes, the mixture was added2-benzofuran-2-yl-ethanol (0.36 g, 2.2 mmol) and stirred at roomtemperature overnight. The mixture was filtered, and the filtrate wasconcentrated and extracted with EtOAc (30 mL) and Na₂CO₃ (20 mL). Theorganic layer was washed with water (20 mL) and brine (20 mL), andconcentrated. The resulting oil was purified on silica gel column togive4-[4-(2-benzofuran-2-yl-ethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester (0.20 g, 21%).

Step 3: To the THF solution (10 mL) of4-[4-(2-benzofuran-2-yl-ethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester (0.7 g, 1.5 mmol), was added potassium tert-butoxide(0.45 mL, 0.45 mmol) at 0° C. The mixture was stirred at 0° C. for 10minutes and was quenched with 1N HCl (5 mL, 5 mmol), followed bysaturated NaHCO₃ (25 mL). The mixture was extracted with EtOAc (50mL×2). The organic layer was washed with water (30 mL) and brine (30mL), dried over MgSO₄, and concentrated. The resulting solid waspurified on silica gel column eluted with CH₂Cl₂/MeOH to give3-[4-(2-benzofuran-2-yl-ethoxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas white solid (0.15 g, 83%). mp: 160-162° C.; HPLC: Waters SymmetryC₁₈, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, gradient to 95/5acetonitrile/0.1% H₃PO₄ in 5 min: t_(R)=5.01 min (99%); ¹H NMR (DMSO-d₆)δ 1.87-1.98 (m, 1H, CHH), 2.37 (qd, J=4.5, 13.2 Hz, 1H, CHH), 2.59 (d,J=1.9 Hz, 1H, CHH), 2.80-2.97 (m, 1H, CHH), 3.29 (t, J=6.2 Hz, 2H, CH₂),4.10-4.36 (m, 2H, CH₂), 4.49 (t, J=6.3 Hz, 2H, CH₂), 5.09 (dd, J=5.1,13.4 Hz, 1H, NCH), 6.74 (s, 1H, Ar), 7.11-7.29 (m, 2H, Ar), 7.29-7.40(m, 2H, Ar), 7.44-7.62 (m, 3H, Ar), 10.96 (s, 1H, NH). ¹³C NMR (DMSO-d₆)δ 22.33, 28.11, 31.18, 44.97, 51.56, 65.86, 103.43, 110.70, 115.01,115.36, 120.52, 122.66, 123.52, 128.42, 129.84, 129.91, 133.31, 153.44,153.99, 155.72, 167.95, 170.96, 172.80; LCMS: 405; Anal Calcd forC₂₃H₂₀N₂O₅+0.06 EtOAc: C, 68.13; H, 5.04; N, 6.84; Found: C, 67.73; H,5.16; N, 6.75.

5.2934-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YLOXY)METHYL)BENZONITRILE

To a mixture of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.25 g, 0.86mmol) and K₂CO₃ (0.38 g, 2.74 mmol) in DMF (40 mL), was slowly added4-(bromomethyl)benzonitrile (0.48 mL, 2.46 mmol). The reaction mixturewas stirred at room temperature overnight. Additional K₂CO₃ (0.38 g,2.74 mmol) was added and the reaction mixture was heated at 80° C.overnight. Acetic acid (5 drops) was added to reaction mixture. Thesolvent was evaporated and the residue was partitioned between ethylacetate (100 mL) and saturated solution of sodium bicarbonate (100 mL).Solid that did not go into solution was filtered and it was stirred inmethanol (400 mL). Solid was then filtered, washed with methanol (100mL) and dried to give4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzonitrileas a white solid (0.31 g, 66% yield): HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, acetonitrile/0.1% H3PO4: gradient10/90 to 90/10 in 15 min; 5 min at 90/10: 10.45 min (98.49%); mp:290-292° C.; 1H NMR (DMSO-d6) δ 1.85-2.12 (m, 1H, CHH), 2.34-2.47 (m,1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.78-3.07 (m, 1H, CHH), 4.13-4.39 (d,J=17.6 Hz, 1H, CHH), 4.47 (d, J=17.6 Hz, 1H, CHH), 5.12 (dd, J=5.1, 13.2Hz, 1H, CH), 5.37 (s, 2H, CH2), 7.32 (dd, J=7.6, 16.7 Hz, 2H, Ar),7.41-7.57 (m, 1H, Ar), 7.69 (d, J=8.1 Hz, 2H, Ar), 7.88 (d, J=8.3 Hz,2H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) 22.37, 31.16, 45.03,51.58, 68.49, 110.60, 114.93, 115.53, 118.67, 128.01, 129.83, 129.97,132.41, 133.40, 142.41, 153.07, 167.90, 170.95, 172.81; LCMS MH=376;Anal Calcd for C₂₁H₁₇N₃O₄+0.1H₂O: C, 66.87, H, 4.60, N, 11.14; Found: C,66.43, H, 4.47, N, 11.05.

5.2943-[4-(4-HEXYLAMINOMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: To the acetonitrile solution (20 mL) of4-carbamoyl-4-[4-(4-chloromethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.7 g, 1.62 mmol), was added hexyl amine (1.07 ml,8.1 mmol). The mixture was stirred at room temperature overnight. Thereaction mixture was concentrated and the resulting oil was used in nextstep without purification.

Step 2: To the DMF solution (10 mL) of4-carbamoyl-4-[4-(4-hexylaminomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester (0.8 g, 1.62 mmol), was added potassium carbonate(0.22 g, 1.62 mmol). The mixture was stirred at 70° C. for 9 hours. Themixture was filtered. The filtrate was concentrated on rota-vap. Theresulting mixture was purified on silica gel column and eluted withCH₂Cl₂/MeOH to give3-[4-(4-hexylaminomethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (84 mg, 12%). mp: 155-157° C. HPLC: Waters SymmetryC-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient acetonitrile/0.1%H₃PO₄ in H₂O from 5/95 to 100/0 in 5 min and stayed at 100/0 for 5 min:t_(R)=5.09 min (96%). ¹H NMR (DMSO-d₆) δ 0.65-0.98 (m, 3H, CH₃),1.11-1.33 (m, 6H, CH₂, CH₂, CH₂), 1.41 (d, J=6.8 Hz, 2H, CH₂), 1.86-2.07(m, 1H, CHH), 2.35-2.47 (m, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.78-3.09(m, 1H, CHH), 3.71 (s, 2H, CH₂), 4.17-4.53 (m, 2H, CH2), 5.10 (dd,J=5.1, 13.2 Hz, 1H, NCH), 5.22 (s, 2H, CH₂), 7.12-7.63 (m, 7H, Ar). 13CNMR (DMSO-d₆) δ 13.84, 21.99, 22.30, 26.35, 28.87, 31.13, 45.04, 48.35,51.53, 52.28, 69.36, 114.94, 115.15, 127.56, 128.15, 129.73, 129.90,133.24, 134.95, 139.89, 153.40, 167.94, 170.91, 172.7; LCMS MH=464. AnalCalcd for C₂₇H₃₃N₃O₄: c, 69.96; H, 7.18; N, 9.06; Found: C, 61.67; H,6.22; N, 7.96.

5.2954-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1-OXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLOXYMETHYL]-N-(2-MORPHOLIN-4-YL-ETHYL)-BENZAMIDE

Step 1: 4-(Chloromethyl)benzoyl chloride (1.452 g, 7.68 mmol) was addedto a stirred solution of 2-morpholinoethanamine (1 g, 7.68 mmol) inacetonitrile (25 mL). The resulting solution was stirred for 2 hours andthe reaction was complete. The reaction mixture concentrated andpurified with ISCO to give4-chloromethyl-N-(2-morpholin-4-yl-ethyl)-benzamide as white solid (1.7g, 78% yield); LCMS MH=283, 285.1H NMR (DMSO-d₆) δ 2.43 (d, J=14.5 Hz,6H, CH₂, CH₂, CH₂), 3.35-3.44 (m, 2H, CH₂), 3.50-3.63 (m, 4H, CH₂, CH₂),4.81 (s, 2H, CH₂), 7.52 (d, J=8.1 Hz, 2H, Ar), 7.83 (d, J=8.3 Hz, 2H,Ar), 8.34-8.49 (m, 1H, NH).

Step 2: To a stirred solution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (400 mg, 1.36mmol), 4-(chloromethyl)-N-(2-morpholinoethyl)benzamide (387 mg, 1.36mmol) and K₂CO₃ (189 mg, 1.36 mmol) in DMF (10 mL), was added DIPEA(0.24 ml, 1.36 mmol) at room temperature. The resulting reaction mixturewas stirred at room temperature for 21 hours and heated at 50° C. for 4days. Then mixture was heated at 80° C. overnight and concentrated forpurification with ISCO to give a white solid, which was triturated inacetonitrile (3 mL) to give4-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yloxymethyl]-N-(2-morpholin-4-yl-ethyl)-benzamideas a white solid (123 mg, 17.7% yield). HPLC: Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient 5-50%. in 10 min(acetonitrile/0.1% H₃PO₄), 7.28 min (97.4%); mp: 193-195° C. ¹H NMR(DMSO-d₆) δ 1.91-2.10 (m, 1H, CHH), 2.36-2.48 (m, 7H, CHH, CH₂, CH₂,CH₂), 2.54-2.65 (m, 1H, CHH), 2.83-3.02 (m, 1H, CHH), 3.34-3.44 (m, 2H,CH₂), 3.51-3.62 (m, 4H, CH₂, CH₂), 4.22-4.53 (m, 2H, CHH, CHH),5.05-5.18 (m, 1H, CHN), 5.32 (s, 2H, CH₂), 7.27-7.37 (m, 2H, Ar),7.44-7.52 (m, 1H, Ar), 7.57 (d, J=8.3 Hz, 2H, Ar), 7.85 (d, J=8.3 Hz,2H, Ar), 8.40 (s, 1H, NH), 10.98 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 22.34,31.18, 36.51, 45.07, 51.58, 53.25, 57.29, 66.16, 68.97, 115.01, 115.35,127.23, 127.29, 129.78, 129.97, 133.34, 134.16, 139.67, 153.27, 165.78,167.94, 170.96, 172.81. LCMS MH=507. Anal. Calcd for C₂₇H₃₀N₄O₆+1.2H₂O:C, 61.40; H, 6.18; N, 10.61; Found: C, 61.10; H, 6.11; N, 10.26.

5.2963-(4-((6-((DIETHYLAMINO)METHYL)BENZOFURAN-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A mixture of ethyl 5-formylbenzofuran-2-carboxylate (1.1 g, 4.8mmol), diethylamine (0.4 g, 5.3 mmol) and acetic acid (0.3 g, 5.5 mmol)in THF (45 mL) was stirred at room temperature for 30 minutes. Sodiumtriacetoxyborohydride (2.0 g, 9.6 mmol) was added and the mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith EtOAc (70 mL) and water (40 mL) and basified with NH₄OH to pH˜11.Layers were separated and aqueous layer was extracted with EtOAc (40mL). Combined EtOAc solution was dried and concentrated. Residue waspurified by chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give ethyl5-(diethylaminomethyl)benzofuran-2-carboxylate (0.9 g, 70% yield): ¹HNMR (CDCl₃) δ 1.05 (t, J=6.9 Hz, 6H), 1.42 (t, J=7.2 Hz, 3H), 2.50-2.75(q, J=7.2 Hz, 4H), 3.64 (s, 2H), 4.40-4.47 (q, J=7.2 Hz, 2H), 7.42-7.53(m, 3H), 7.62 (d, J=0.9 Hz, 1H).

Step 2: A solution of ethyl5-(diethylaminomethyl)-benzofuran-2-carboxylate (0.9 g, 3.3 mmol) in THF(15 mL) was added slowly to a stirred solution of LiAlH₄/THF (1M, 4.3mL, 4.3 mmol) in THF (10 mL) at 5° C. The reaction mixture was stirredat 5° C. for 30 minutes then quenched with sat. Na₂CO₃ (30 mL). Themixture was stirred with CH₂Cl₂ (50 mL) and aqueous layer was extractedwith CH₂Cl₂ (3×40 mL). Combined CH₂Cl₂ solution was washed with brine(40 mL) and dried. The solvent was removed and the residue was purifiedby chromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give[5-(diethylaminomethyl)benzofuran-2-yl]methanol (0.6 g, 87%); ¹H NMR(CDCl₃) δ 1.05 (t, J=7.2 Hz, 6H), 2.50-2.57 (q, J=7.2 Hz, 4H), 2.93 (b,1H), 3.62 (s, 2H), 4.71 (s, 2H), 6.56 (d, J=0.3 Hz, 1H), 7.21-7.24 (dd,J=1.8 and 8.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H).

Step 3: Diisopropyl azodicarboxylate (0.8 g, 4.2 mmol) was added to astirred suspension of triphenylphosphine-polymer bound (3.5 g, 4.4 mmol)in THF (40 mL) at 3-5° C. After stirred at 3° C. for 10 minutes, asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (0.8 g, 2.8mmol) and [5-(diethylaminomethyl)benzofuran-2-yl]methanol (0.7 g, 2.8mmol) in THF (60 mL) was added at 3-6° C. After stirred at 3° C. for 5minutes, mixture was stirred at room temperature overnight. The reactionmixture was filtered and solid was washed with CH₂Cl₂ (40 mL). Filtratewas concentrated and the residue was dissolved in CH₂Cl₂ (100 mL) andwashed with sat. NaHCO₃ (40 mL), water (40 mL), and brine (40 mL), anddried. The solvent was removed and the residue was purified bychromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-((5-((diethylamino)methyl)benzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.7, 47% yield): ¹H NMR (CDCl₃) δ 1.05 (t, J=7.2 Hz, 6H), 2.12-2.44 (m,4H), 2.50-2.57 (q, J=7.2 Hz, 4H), 3.62-3.64 (m, 5H), 4.40 (d, J=17.4 Hz,1H), 4.45 (d, J=17.4 Hz, 1H), 4.87-4.92 (dd, J=5.7 and 8.7 Hz, 1H), 5.23(s, 2H), 5.49 (s, 1H), 6.40 (s, 1H), 6.77 (s, 1H), 7.15-7.18 (dd, J=2.4and 6.6 Hz, 1H), 7.22-7.29 (m, 1H), 7.39-7.46 (m, 3H), 7.53 (d, J=0.9Hz, 1H).

Step 4: A mixture of methyl5-amino-4-(4-((5-((diethylamino)methyl)benzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.7 g, 1.3 mmol) and K₂CO₃ (0.2 g, 1.3 mmol) in DMF (10 mL) was heatedat 80° C. oil bath for 6 hours. The reaction mixture was cooled andconcentrated. Residue was stirred with EtOAc (10 mL) and water (20 mL).Solid was collected and purified by chromatography (SiO₂, CH₃OH: CH₂Cl₂3: 97 to 5: 95) to give3-(4-((6-diethylamino)methyl)benzofuran-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.3 g, 51% yield): mp 193-195° C.; ¹H NMR (DMSO-d₆) δ 0.97 (t, J=6.9Hz, 6H), 1.94-1.98 (m, 1H), 2.39-2.58 (m, 6H), 2.84-2.94 (m, 1H), 3.59(s, 2H), 4.25 (d, J=17.7 Hz, 1H), 4.35 (d, J=17.7 Hz, 1H), 5.07-5.13(dd, J=5.1 and 13.2 Hz, 1H), 5.41 (s, 2H), 7.07 (s, 1H), 7.26-7.29 (dd,J=1.2 and 8.4 Hz, 1H), 7.34-7.37 (dd, J=0.9 and 6.9 Hz, 1H), 7.46-7.56(m, 4H), 10.96 (s, 1H); ¹³C NMR (DMSO-d₆) δ 11.59, 22.28, 31.16, 45.03,45.96, 51.55, 56.73, 62.55, 107.05, 110.68, 115.11, 115.64, 121.08,125.66, 127.40, 129.81, 129.94, 133.42, 134.69, 152.67, 152.98, 153.68,167.88, 170.93, 172.79; Calcd for C₂₇H₂₉N₃O₅+0.2H₂O: C, 67.68; H, 6.18;N, 8.77; Found: C, 67.70; H, 5.94; N, 8.63.

5.2973-(4-((6-((DIETHYLAMINO)METHYL)BENZO[B]THIOPHEN-2-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: A suspension mixture of rhodanine (6.0 g, 45 mmol) and sodiumacetate (11.3 g, 137 mmol) in glacial acetic acid (60 mL) was heated at75° C. oil bath. P-tolualdehyde (5.8 g, 47.9 mmol) was added slowly andmixture was heated at 120° C. for 1 hour. The mixture was cooled to roomtemperature and poured into ice water (400 mL). After stirred for 30minutes, mixture was filtered to give 14 g of orange solid. Solid wasdissolved in 5% NaOH (200 mL) and heated in 80° C. oil bath for 1 hourthen cooled to room temperature. The mixture was acidified withconcentrated HCl and solid was collected to give2-mercapto-3-p-tolylacrylic acid (6.4 g, 73% yield): ¹H NMR (DMSO-d₆) δ2.34 (s, 3H), 7.28-7.31 (d, J=8.1 Hz, 2H), 7.57-7.60 (d, J=8.1 Hz, 2H),7.71 (s, 1H).

Step 2: A mixture of 2-mercapto-3-p-tolylacrylic acid (1.5 g, 7.7 mmol)and I₂ (2.9 g, 11.6 mmol) in 1,4-dioxane (12 mL) was irradiated inmicrowave at 160° C. for 12 minutes. The mixture was cooled to roomtemperature and poured into sat. sodium bisulfite (300 mL). Solid wascollected and dried to give 6-methylbenzo[b]thiophene-2-carboxylic acid(1.8 g, 100%). Compound was used in next reaction without furtherpurification.

Step 3: Concentrated H₂SO₄ (5 mL) was added to a stirred mixture of6-methylbenzo[b]thiophene-2-carboxylic acid (4.4 g, 23.2 mmol) inmethanol (100 mL). The resulting mixture was heated to reflux for 3hours. The mixture was cooled and concentrated. Residue was dissolved inCH₂Cl₂ (150 mL) and washed with 2N NaOH (40 mL), water (2×40 mL), andbrine (40 mL), and dried. The solvent was removed and the residue waspurified by chromatography (SiO₂, EtOAc: Hexane 1: 9) to give methyl6-methylbenzo[b]thiophene-2carboxylate (2.9 g, 60% yield): ¹H NMR(CDCl₃) δ 2.49 (s, 3H), 3.93 (s, 3H), 7.20-7.26 (m, 1H), 7.65 (s, 1H),7.74 (d, J=6 Hz, 1H), 8.01 (s, 1H).

Step 4: N-bromosuccinimide (4.0 g, 22.5 mmol) was added to a stirredsolution of methyl 6-methylbenzo[b]thiopnene-2-carboxylate (3.6 g, 17.4mmol) in CCl₄ (55 mL). The reaction mixture was heated at a 75° C. oilbath with a 300 W bulb shining for 17 hours. The reaction mixture wascooled and filtered and filtrate was washed with water (2×40 mL) andbrine (40 mL), and dried. The solvent was removed and the residue waspurified by chromatography (SiO₂, EtOAc: Hexane 1:9) to give methyl6-(bromomethyl)benzo[b]thiophene-2-carboxylate (2.2 g, 44% yield): ¹HNMR (CDCl₃) δ 3.90 (s, 3H), 4.40 (s, 2H), 7.39-7.44 (m, 4H).

Step 5: A mixture of diethylamine (1.0 g, 13.7 mmol), K₂CO₃ (3.5 g, 25.3mmol) and 18-crown-6 (catalytic amount) in acetone (15 mL) was heated at35° C. oil bath. A solution of methyl6-(bromomethyl)benzo[b]thiophene-2-carboxylate (1.6 g, 5.6 mmol) inacetone (15 mL) was added. The reaction mixture was stirred at 45° C.oil bath for 3 hours and then cooled to room temperature. The mixturewas filtered and filtrate was concentrated. Residue was dissolved inEtOAc (70 mL) and washed with water (2×30 mL) and brine (30 mL), anddried. The solvent was removed and the residue was purified bychromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl6-[(diethylamino)methyl]benzo[b]thiophene-2-carboxylate (1.3 g, 84%yield): ¹H NMR (CDCl₃) δ 1.06 (t, J=6.9 Hz, 6H), 2.52-2.59 (q, J=7.2 Hz,4H), 3.68 (s, 2H), 3.93 (s, 3H), 7.38-7.41 (dd, J=1.2 and 8.4 Hz, 1H),7.78-7.84 (m, 2H), 8.03 (s, 1H).

Step 6: A solution of methyl6-[(diethylamino)methyl]benzo[b]thiophene-2-carboxylate (1.3 g, 4.7mmol) in THF (20 mL) was added slowly to a stirred solution ofLiAlH₄/THF (1M, 6 mL, 6 mmol) in THF (10 mL) at 3-6° C. The resultingsolution was stirred at 3° C. for 30 minutes and then quenched withwater (5 mL). The mixture was stirred with CH₂Cl₂ (40 mL) and sat.NaHCO₃ (20 mL). The aqueous layer was extracted with CH₂Cl₂ (2×30 mL)and combined CH₂Cl₂ solution was washed with water (30 mL) and brine (30mL), and dried. The solvent was removed and the residue was purified bychromatography (SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give[6-[(diethylamino)methyl]benzo[b]thiophen-2-yl]methanol (1.0 g, 84%yield): ¹H NMR (CDCl₃) δ 1.05 (t, J=6 Hz, 6H), 2.51-2.58 (q, J=6 Hz,4H), 2.72 (b, 1H), 3.65 (s, 2H), 4.87 (s, 2H), 7.13 (d, J=3 Hz, 1H),7.29-7.32 (d, J=9 Hz, 1H), 7.61 (d, J=9 Hz, 1H), 7.77 (s, 1H).

Step 7: Diisopropyl azodicarboxylate (0.9 g, 4.3 mmol) was added to astirred suspension of triphenylphosphine-polymer bound (3.4 g, 5.4 mmol)in THF (40 mL) at 3-5° C. After stirred at 3° C. for 10 minutes, asolution of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.1 g, 3.6mmol) and [6-[(diethylamino)methyl]benzo[b]thiophen-2-yl]methanol (0.9g, 3.6 mmol) in THF (80 mL) was added slowly at 3-6° C. The resultingmixture was stirred at room temperature overnight. The mixture wasfiltered and solid was washed with CH₂Cl₂ (40 mL). Filtrate wasconcentrated and the residue was dissolved in CH₂Cl₂ (100 mL) and washedwith sat. NaHCO₃ (30 mL), water (30 mL), and brine (30 mL), and dried.The solvent was removed and the residue was purified by chromatography(SiO₂, CH₃OH: CH₂Cl₂ 3: 97) to give methyl5-amino-4-(4-((6-((diethylamino)methyl)benzo[b]thiophen-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.7 g, 35% yield).

Step 8: A mixture of methyl5-amino-4-(4-((6-((diethylamino)methyl)benzo[b]thiophen-2-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.7 g, 1.2 mmol) and K₂CO₃ (0.2 g, 1.2 mmol) in DMF (10 mL) was heatedat 80° C. oil bath for 3 hours. The reaction mixture was cooled anddiluted with EtOAc (80 mL) and washed with water (3×35 mL) and brine (35mL), and dried. The solvent was removed and the residue wascrystallizing from hot EtOAc (10 mL) to give3-(4-((6-((diethylamino)methyl)benzo[b]thiophen-2-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.3 g, 44% yield): mp 190-192° C.; 1H NMR (DMSO-d₆) δ 0.98 (t, J=6 Hz,6H), 1.96-2.02 (m, 1H), 2.43-2.60 (m, 6H), 2.90-2.93 (m, 1H), 3.32 (s,2H), 4.29 (d, J=18 Hz, 1H), 4.38 (d, J=18 Hz, 1H), 5.08-5.14 (dd, J=3and 12 Hz, 1H), 5.57 (s, 2H), 7.73-7.53 (m, 5H), 7.75-7.85 (m, 2H),10.97 (s, 1H); ¹³C NMR (DMSO-d₆) δ 11.60, 22.31, 31.18, 45.04, 46.11,51.59, 56.82, 65.28, 115.26, 115.62, 121.94, 123.35, 123.52, 125.56,129.79, 130.05, 133.40, 137.83, 139.42, 152.87, 167.89, 170.95, 172.80;Calcd for C₂₇H₂₉N₃O₄S+0.2H₂O: C, 65.49; H, 5.98; N, 8.49; S, 6.48;Found: C, 65.25; H, 5.82; N, 8.38; S, 6.63.

5.2983-(4-(4-(8-OXA-3-AZABICYCLO[3.2.1]OCTAN-3-YLMETHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Polymer-supported triphenylphosphine (1.6 mmol/g, 14.2 g, 22.73mmol) was added to a stirred suspension of tert-butyl5-amino-2-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (3.8 g, 11.36mmol) in THF (140 mL) at 0° C., followed by diisopropyl azodicarboxylate(4.6 g, 22.73 mmol). After stirring for 10 minutes,(4-(chloromethyl)phenyl)methanol (2.67 g, 17.05 mmol) was added. Themixture was stirred at room temperature overnight and filtered. Theresin was washed with dichloromethane (2×70 mL). The combined filtrateswere concentrated in vacuo to give a syrup which was partitioned betweenEtOAc (300 ml) and water (100 ml). The organic layer was washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to give a crude productas yellow oil. The crude was purified by ISCO (330 g column, MeOH/CH₂Cl₂gradient from 0% to 5% in 50 min) to give tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(4 g, 74% yield); ¹H NMR (DMSO-d₆) δ 1.39 (s, 9H, CH₃, CH₃, CH₃), 2.07(d, J=1.1 Hz, 4H, CH₂, CH₂), 4.43 (s, 2H, CH₂), 4.64-4.75 (m, 1H, CH),4.78 (s, 2H, CH₂), 5.27 (s, 2H, CH₂), 6.67-6.86 (m, 1H, NHH), 7.17-7.27(m, 1H, NHH), 7.32 (d, J=2.6 Hz, 2H, Ar), 7.49 (d, J=5.1 Hz, 5H, Ar).

Step 2: To a solution of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(500 mg, 1.06 mmol) in acetonitrile (10 ml), were added8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (190 mg, 1.27 mmol) andN,N-diisopropylethylamine (410 mg, 3.17 mmol). The mixture formed wasstirred at room temperature overnight. The solvent was evaporated undervacuo. The residue was taken in ethyl acetate (100 ml), washed withwater (10 ml) and brine, and dried over MgSO₄. The solvent wasevaporated to give tert-butyl2-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(560 mg, 96% yield). ¹H NMR (DMSO-d₆) δ 1.39 (s, 9H, CH₃, CH₃, CH₃),1.66-1.78 (m, 2H, CH₂), 1.82-1.92 (m, 2H, CH₂), 1.97-2.30 (m, 6H, CH₂,CH₂, CH₂), 3.44 (s, 2H, CH₂), 4.13-4.28 (m, 2H, CH, CH), 4.42 (s, 2H,CH₂), 4.63-4.80 (m, 1H, CH), 5.23 (s, 2H, CH₂), 6.65-6.87 (m, 1H, NHH),7.15-7.27 (m, 1H, NHH), 7.33 (d, J=9.3 Hz, 4H, Ar), 7.41-7.54 (m, 3H,Ar).

Step 3: To a slurry of tert-butyl2-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(560 mg, 1.019 mmol) in THF (20 ml), was added potassium tert-butoxide(137 mg, 1.223 mmol) at 0° C. The mixture was stirred at 0° C. for 10minutes, warmed up to room temperature and stirred overnight. Thereaction was quenched with acetic acid (3 ml), THF was removed undervacuum, and the residue was partitioned between ethyl acetate (70 ml)and saturated sodium bicarbonate (10 ml). The precipitate formed wasfiltered and the filtrate was washed with brine and dried over magnesiumsulfate. The solvent was evaporated and the crude was purified by prepHPLC to give3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (80 mg, 17% yield); mp: 228-230° C.; ¹H NMR (DMSO-d₆) δ1.58-2.31 (m, 6H, 6×CHH), 2.31-2.50 (m, 2H, CHH, CHH), 2.58 (d, J=18.3Hz, 2H, CHH, CHH), 2.82-3.03 (m, 1H, CHH), 3.12 (br. s., 1H, CHH),3.39-3.60 (m, 2H, CH₂), 3.92-4.76 (m, 4H, CH₂, CH, CH), 5.11 (dd, J=5.0,13.1 Hz, 1H, CH), 5.25 (br. s., 2H, CH₂), 7.12-7.84 (m, 7H, Ar), 10.97(s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.34, 27.94, 31.16, 45.06, 51.56,58.19, 60.95, 69.25, 73.58, 114.94, 115.26, 127.64, 129.80, 129.93,133.30, 137.72, 153.43, 157.78, 158.20, 162.96, 167.97, 170.96, 172.81;LCMS MH=476; HPLC: Waters Xterra C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240nm, Gradient (acetonitrile/0.1% HCOONH₄) 5/95 to 95/5 in 5 min, 95/5 10min: t_(R)=5.26 (100%).

5.2993-(4-(4-(8-OXA-3-AZABICYCLO[3.2.1]OCTAN-3-YLMETHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: To a solution of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(500 mg, 1.06 mmol) in acetontrile (10 ml) was added8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (190 mg, 1.27 mmol) andN,N-Diisopropylethyl-amine (410 mg, 3.17 mmol). The formed mixture wasstirred at room temperature overnight. The solvent was evaporated undervacuo. The residue was taken in ethyl acetate (100 ml) and washed withwater (10 ml), brine, dried over MgSO₄, the solvent was evaporated togive tert-butyl2-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(560 mg, 96% yield). ¹H NMR (DMSO-d₆) δ 1.39 (s, 9H, CH₃, CH₃, CH₃),1.66-1.78 (m, 2H, CH₂), 1.82-1.92 (m, 2H, CH₂), 1.97-2.30 (m, 6H, CH₂,CH₂, CH₂), 3.44 (s, 2H, CH₂), 4.13-4.28 (m, 2H, CH, CH), 4.42 (s, 2H,CH₂), 4.63-4.80 (m, 1H, CH), 5.23 (s, 2H, CH₂), 6.65-6.87 (m, 1H, NHH),7.15-7.27 (m, 1H, NHH), 7.33 (d, J=9.3 Hz, 4H, Ar), 7.41-7.54 (m, 3H,Ar).

Step 2: To a slurry of tert-butyl2-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(560 mg, 1.019 mmol) in THF (20 ml) was added potassium tert-butoxide(137 mg, 1.223 mmol) at 0° C. The mixture was stirred at 0° C. for 10minutes, warmed up to room temperature and stirred overnight. Thereaction was quenched with acetic acid (3 ml), THF was removed undervacuum, the residue was partitioned between ethyl acetate (70 ml) andsaturated sodium bicarbonate (10 ml), the formed precipitate wasfiltered to give2-((4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)benzyl)oxy)-6-((2,6-dioxopiperidin-3-yl)carbamoyl)benzoicacid (210 mg, 38% yield). ¹H NMR (DMSO-d₆) δ 1.65-1.79 (m, 2H, CHH,CHH), 1.81-1.90 (m, 2H, CHH, CHH), 1.97 (d, J=3.4 Hz, 1H, CHH), 2.04(br. s., 1H, CHH), 2.16 (d, J=1.7 Hz, 1H, CHH), 2.20 (d, J=1.7 Hz, 1H,CHH), 2.41-2.50 (m, 2H, CHH, CHH), 2.57 (br. s., 1H, CHH), 2.77 (s, 1H,CHH), 3.42 (s, 2H, CH₂), 4.19 (dd, J=2.0, 4.2 Hz, 2H, CH, CH), 4.70 (s,1H, CH), 5.16 (s, 2H, CH₂), 7.17-7.35 (m, 4H, Ar), 7.35-7.53 (m, 3H,Ar), 8.72 (d, J=8.5 Hz, 1H, NH), 10.85 (s, 1H, NH).

Step 3: The mixture of2-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)benzyloxy)-6-(2,6-dioxopiperidin-3-ylcarbamoyl)benzoicacid (210 mg, 0.41 mmol) and triethyl amine (83 mg, 0.82 mmol) in aceticacid (5 ml) was refluxed overnight. The mixture was cooled to roomtemperature, acetic acid was removed under vacuum, the residue waspartitioned between EtOAc (50 ml) and saturated NaHCO₃, the organiclayer was washed with water, brine, dried (MgSO₄) and concentrated invacuo to give a crude. The crude was reslurried in ether (2×5 ml) andfiltered to give4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylmethyl)benzyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(120 mg, 78% yield); m.p: 196-198° C.; ¹H NMR (DMSO-d₆) δ 1.56-1.76 (m,2H, CHH, CHH), 1.76-1.87 (m, 2H, CHH, CHH), 1.88-2.05 (m, 1H, CHH), 2.12(d, J=10.6 Hz, 2H, CHH, CHH), 2.41 (br. s., 2H, CHH, CHH), 2.45-2.63 (m,2H, CHH, CHH), 2.79 (d, J=11.7 Hz, 1H, CHH), 3.37 (s, 2H, CH₂), 4.12 (d,J=1.7 Hz, 2H, CH, CH), 5.02 (dd, J=5.4, 12.7 Hz, 1H, CH), 5.28 (s, 2H,CH₂), 7.27 (d, J=7.9 Hz, 2H, Ar), 7.40 (dd, J=3.1, 7.6 Hz, 3H, Ar), 7.53(d, J=8.5 Hz, 1H, Ar), 7.69-7.85 (m, 1H, Ar), 11.04 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 21.95, 28.29, 30.90, 48.73, 58.06, 61.11, 69.95, 73.69,115.48, 16.56, 120.19, 127.28, 128.56, 133.24, 134.68, 136.97, 155.53,165.29, 166.75, 169.87, 172.71; HPLC: Waters Xterra C-18, 3.9×150 mm, 5μm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% HCOONH₄ t_(R)=3.97 (100%); Anal.Calcd for C₂₇H₂₇N₃O₇+0.1H₂O; C, 66.00; H, 5.58; N, 8.55; Found: C,65.96; H, 5.68; N, 8.27.

5.3003-(4-(4-(3-OXA-8-AZABICYCLO[3.2.1]OCTAN-8-YLMETHYL)BENZYLOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: tert-butyl2-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate

To a suspension of tert-butyl5-amino-2-(4-(4-(chloromethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(500 mg, 1.06 mmol) in MeCN (10 mL), was added(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (316 mg, 2.114mmol) and N,N-diisopropylethylamine (0.41 mL, 2.33 mmol). The mixturewas warmed up to 60° C. and stirred overnight. After ˜15 h, the reactionmixture was concentrated to dryness and the solid residue waspartitioned between EtOAc (150 mL) and 1N NaHCO₃ (30 mL). The aqueouslayer was washed with additional EtOAc (150 mL). The organic layers werecombined, washed with brine, dried (Na₂SO₄), and concentrated in vacuoand then dried in a vacuum oven at 60° C. to a provide tert-butyl2-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoateas a white solid (580 mg, 100% yield); LC/MS M+H=550. The solid was usedin the next step without further purification.

Step 2: tert-Butyl2-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate

To a cooled solution of tert-butyl2-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoate(580 mg, 1.06 mmol) in THF (10 mL) in an ice bath, was added KO^(t)Bu(154 mg, 1.38 mmol) as a solid in one portion. The ice bath wasimmediately removed and the reaction mixture was stirred at roomtemperature for 90 min. The reaction mixture was cooled in an ice bathand quenched by addition of acetic acid (0.162 mL, 2.82 mmol). Thevolatiles were removed in vacuo to give a white solid that waspartitioned between EtOAc (125 mL) and 1N NaHCO₃ (30 mL). The aqueouslayer was extracted with additional EtOAc (˜75 mL). The combined organiclayer was washed with brine, dried (Na₂SO₄), and concentrated in vacuoto give an off-white solid (400 mg crude yield). The solid wastriturated with Et₂O (40 mL) with the aid of sonication, collected onfilter funnel and washed with additional Et₂O. A similar trituration wascarried out with water (35 mL) and the solid was collected on a filterfunnel, suction dried, then placed in vacuum oven at 60° C. for severalhours to give tert-butyl2-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-amino-5-oxopentanoateas a white solid (305 mg, 61% yield): HPLC: Waters Symmetry Cis, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 6.81 min (95.0%);mp: 243-245° C.; ¹H NMR (DMSO-d₆) δ 1.69-1.81 (m, 2H, CH₂), 1.86-2.06(m, 3H, 3×CHH), 2.33-2.48 (m, 1H, CHH), 2.52-2.64 (m, 1H, CHH),2.81-3.02 (m, 3H, 3×CHH), 3.35-3.46 (m, 4H, CH₂, CHH, CHH), 3.48-3.59(m, 2H, CHH, CHH), 4.25 (d, J=17.4 Hz, 1H, CHH), 4.42 (d, J=17.6 Hz, 1H,CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.22 (s, 2H, CH₂), 7.27-7.55(m, 7H, Ar), 10.97 (s, 1H, Ar); ¹³C NMR (DMSO-d₆) δ 22.33, 24.56, 31.18,45.06, 51.55, 56.42, 59.89, 69.41, 72.51, 114.94, 115.19, 127.61,128.60, 129.78, 129.93, 133.28, 134.99, 139.32, 153.49, 167.99, 170.96,172.81; LC/MS M+H=476; Anal Calcd for C₂₇H₂₉N₃O₅+0.17H₂O+0.26 EtOAc: C,67.15; H, 6.31; N, 8.38; Found: C, 67.15; H, 6.23; N, 8.49.

5.3013-[5-CHLORO-4-(4-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

Step 1: Preparation of 4-Chloro-3-hydroxy-2-methyl-benzoic acid methylester

To the stirred solution of 4-chloro-3-hydroxy-2-methylbenzoic acid (2.5g, 13.40 mmol) in MeOH (20 ml) was added sulfuric acid (0.263 g, 2.68mmol). The resulting solution was reacted at 62° C. for two days. Thereaction mixture was concentrated to give brown solution (30 mL), towhich was added water (80 mL). The mixture was stirred and light brownsolid precipitated out. The mixture was extracted with EtOAc (100 mL).Organic layer was concentrated and purified by silica gel column (120 gEtOAc/Hexanes) to give 4-Chloro-3-hydroxy-2-methyl-benzoic acid methylester as a white solid (6.9 g, 74% yield). It was used in the next stepwithout further work or purification.

Step 2: Preparation of3-(tert-Butyl-dimethyl-silanyloxy)-4-chloro-2-methyl-benzoic acid methylester

To a stirred solution of methyl 4-chloro-3-hydroxy-2-methylbenzoate(6.34 g, 31.6 mmol) and 1H-imidazole (5.38 g, 79 mmol) in DMF (60 ml) ina 250 ml RBF in an ice-bath was added tert-butylchlorodimethylsilane(5.24 g, 34.8 mmol). After 20 minutes, the ice-bath was removed and themixture was stirred at room temperature for 2 hours. Ice-water (50 ml)was added to the mixture, the resulting precipitate was extracted withethyl acetate (2×40 ml). The combined EtOAc phases were washed withwater (40 ml), brine (40 ml), and concentrated to an oil (14.08 g),which was purified by silica gel column to give3-(tert-Butyl-dimethyl-silanyloxy)-4-chloro-2-methyl-benzoic acid methylester as an oil, 8.38 g, 84% yield. The product was used in the nextstep without further purification.

Step 3: Preparation of2-Bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-4-chloro-benzoic acidmethyl ester

To a solution of methyl3-(tert-butyldimethylsilyloxy)-4-chloro-2-methylbenzoate (8.38 g, 26.6mmol) in methyl acetate (50 ml, 26.6 mmol) was added1-bromopyrrolidine-2,5-dione (4.74 g, 26.6 mmol) at room temperature.The mixture was heated to 50° C. for one hour. The reaction mixture wascooled to room temperature and washed with 50% sodium sulfite (Na₂SO₃,50 ml), water (50 ml) and brine (50 ml). The organic phase was dried inMgSO₄ and concentrated to an oil, which was purified by silica gelcolumn (120 g, 1% EtOAc in Hex gradient to 5% in 18 minutes) to give2-Bromomethyl-3-(tert-butyl-dimethyl-silanyloxy)-4-chloro-benzoic acidmethyl ester as an oil (9.53 g, 91% yield). The product was used in thenext step without further purification.

Step 4: Preparation of4-[4-(tert-Butyl-dimethyl-silanyloxy)-5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester

To a stirred solution of methyl2-(bromomethyl)-3-(tert-butyldimethylsilyloxy)-4-chlorobenzoate (9.5 g,24.13 mmol) in acetonitrile (90 ml) at room temperature was added(S)-methyl 4,5-diamino-5-oxopentanoate hydrochloride (5.22 g, 26.5mmol). To the suspension was slowly addedN-ethyl-N-isopropylpropan-2-amine (8.37 ml, 50.7 mmol). The suspensionwas heated at 40° C. for 24 hours. Solvent was evaporated to give ayellow oil, which was stirred in ether (150 ml) overnight. Thesuspension was filtered and rinsed with extra diethyl ether (50 ml) togive a light yellow solid and the filtrate. The filtrated was washedwith 1N HCl (50 ml), saturated sodium bicarbonate (80 ml), brine (50ml). The ether phase was evaporated to give4-[4-(tert-Butyl-dimethyl-silanyloxy)-5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester as an oil, 8.18 g, 76% crude yield. It was used in thenext step without further purification.

Step 5: Preparation of4-Carbamoyl-4-(5-chloro-4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyricacid methyl ester

To a stirred solution of (S)-methyl5-amino-4-(4-(tert-butyldimethylsilyloxy)-5-chloro-1-oxoisoindolin-2-yl)-5-oxopentanoate(8.16 g, 18.50 mmol) in DMF (25 ml) and Water (10 ml) in an ice bath wasadded potassium carbonate (1.279 g, 9.25 mmol). The mixture was stirredat room temperature for one hour. To the brown mixture was addedacetonitrile (15 ml) and stirred at room temperature for 10 minutes.Solvent was evaporated. The resulting oil was purified by silica gelcolumn (MeOH/CH₂Cl₂, 0.5% grad to 8% in 60 min) to give4-Carbamoyl-4-(5-chloro-4-hydroxy-1-oxo-1,3-dihydro-isoindol-2-yl)-butyricacid methyl ester as an off-white solid (4.62 g, 76% yield). It was usedin the next step without further purification.

Step 6: Preparation of4-[4-(4-Bromomethyl-benzyloxy)-5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl]-4-carbamoyl-butyricacid methyl ester

A mixture of methyl5-amino-4-(5-chloro-4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (4.6g, 14.08 mmol). 1,4-bis(bromomethyl)benzene (11.15 g, 42.2 mmol) andpotassium carbonate (1.946 g, 14.08 mmol) in acetonitrile (70 ml) wasstirred at room temperature for 10 min then heated at 50° C. for 5hours. The reaction mixture was cooled to room temperature, filtered andrinsed with acetonitrile to give a gel-like white solid. The filtratewas purified by silica gel column (MeOH/CH₂Cl₂) to a white solid (1.17g, 16% yield). It was used in the next step without furtherpurification.

Step 7: Preparation of4-Carbamoyl-4-[5-chloro-4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-butyricacid methyl ester

To a stirred suspension of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-5-chloro-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.436 g, 0.855 mmol) in acetonitrile (10 ml) at room temperature wasadded morpholine (0.745 ml, 8.55 mmol) and stirred for one hour. Thesolvent was evaporated to give an oil, which was stirred in water (15ml) and EtOAc (20 ml). The mixture was washed with water (2×30 ml),brine (15 ml), dried and concentrated to give a clear oil (0.46 g, 104%crude yield). It was used in the next step without further purification.

Step 8: Preparation of3-[5-Chloro-4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione

To a stirred solution of methyl5-amino-4-(5-chloro-4-(4-(morpholinomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.44 g, 0.853 mmol) in THF (10 ml) in a 0° C. ice-bath was addedpotassium 2-methylpropan-2-olate (0.192 g, 1.706 mmol) and stirred for10 minutes. The reaction was quickly quenched with 1 N HCl to pH ˜4, andneutralized with saturated NaHCO₃ to pH ˜7. The mixture was extractedwith EtOAc (2×30 ml), dried and evaporated to a white solid, which waspurified by silica gel column to give3-[5-Chloro-4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (72 mg, 17% yield); mp, 224-226° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 jpm, 1 mL/min, 240 nm, gradient from 10/90to 95/5 in 5 min, isocratic at 95/5 in 5 min (CH₃CN/0.1% H₃PO₄), 4.62min (98.7%). ¹H NMR (DMSO-d₆) δ 1.92-2.05 (m, 1H, CHH), 2.26-2.46 (m,5H, CHH, CH₂, CH₂), 2.55-2.67 (m, 1H, CHH), 2.83-3.01 (m, 1H, CHH), 3.47(s, 2H, CH₂), 3.52-3.62 (m, 4H, CH₂, CH₂), 4.39-4.66 (m, 2H, CH₂), 5.11(dd, J=5.1, 13.2 Hz, 1H, NCH), 5.21 (s, 2H, CH₂), 7.29-7.39 (m, 2H, Ar),7.41-7.53 (m, 3H, Ar), 7.66 (d, J=8.1 Hz, 1H, Ar), 11.02 (s, 1H, NH). ¹HNMR (DMSO-d₆)¹³C NMR (DMSO-d₆) δ 22.30, 31.11, 45.79, 51.68, 53.14,62.07, 66.17, 73.52, 118.96, 128.10, 128.95, 130.65, 132.74, 133.96,135.16, 138.06, 149.42, 166.80, 170.69, 172.80. LC/MS (M+1)⁺=484; AnalCalcd for C₂₅H₂₆N₃O₅Cl: C, 62.05; H, 5.42; N, 8.68; Cl, 7.33; Found: C,61.93; H, 5.42; N, 8.61; Cl, 7.22.

5.3023-[5-METHYL-4-(4-MORPHOLIN-4-YLMETHYL-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

A mixture of3-(5-chloro-4-(4-(morpholinomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.2 g, 0.413 mmol), tetrakis(triphenylphosphine)palladium (0) (0.096 g,0.083 mmol) was flushed with nitrogen, and added tetramethylstannane(0.114 ml, 0.827 mmol) in Toluene (3 ml) and DMF (1 ml). It was heatedin a 2-5 ml microwave vial to 130° C. from 12:20 μm for 2 hours. Themixture was purified by preparative HPLC (Water/MeCN, all with 0.1%HCOOH) to give3-[5-Methyl-4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (66 mg, 20% yield); mp, 232-234° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, gradient from 10/90to 70/30 in 5 min, isocratic at 70/30 in 5 min (CH₃CN/0.1% H₃PO₄), 4.78min (96.3%). ¹H NMR (DMSO-d₆) δ 1.90-2.07 (m, 1H, CHH), 2.23-2.48 (m,8H, CHH, CH₂CH₂, CH₃), 2.55-2.67 (m, 1H, CHH), 2.83-3.02 (m, 1H, CHH),3.42-3.50 (m, 2H, CH₂), 3.52-3.66 (m, 4H, CH₂CH₂), 4.35-4.64 (m, 2H,CH₂), 5.01-5.19 (m, 3H, NCH, CH₂), 7.26-7.52 (m, 6H, Ar), 11.00 (s, 1H,NH). ¹³C NMR (DMSO-d₆) δ 16.47, 22.42, 31.18, 45.77, 51.55, 53.15,62.13, 66.20, 72.82, 117.80, 127.97, 128.98, 131.30, 131.89, 133.74,135.93, 137.80, 151.86, 167.74, 170.95, 172.90. LC/MS m/e=464. AnalCalcd for C₂₆H₂₉N₃O₅: C, 67.37; H, 6.31; N, 9.07; Found: C, 67.07; H,6.24; N, 9.04.

5.3033-(4-((3-((METHYLAMINO)METHYL)ISOXAZOL-5-YL)METHOXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: (5-(((tert-Buty dimethylsilyl)oxy)methy)isoxazol-3-yl)methanol

Sodium borohydride (0.596 g, 15.77 mmol) was added to a stirred mixtureof ethyl 5-((tert-butyldimethylsilyloxy)methyl)isoxazole-3-carboxylate(4.5 g, 15.77 mmol) in ethanol (25 mL), and the mixture stirred at roomtemperature for 4 h. Water (50 mL) was added and the mixture wasevaporated to remove the ethanol. The remaining aqueous was extractedwith EtOAc (2×75 mL), and the combined organic layers were washed withbrine (100 mL), dried (MgSO₄), and evaporated, providing 3.67 g as acolorless oil; 1H NMR (CDCl₃) δ 0.12 (s, 6H), 0.92 (s, 9H), 4.70-4.82(m, 4H), 6.25 (s, 1H).

Step 2:3-(Bromomethyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)isoxazole

A solution of(5-((tert-butyldimethylsilyloxy)methyl)isoxazol-3-yl)methanol (3.47 g,14.26 mmol) in dichloromethane (25 mL) was cooled to 0° C., andtriphenylphoshine (4.11 g, 15.68 mmol) and carbon tetrabromide (4.49 g,13.54 mmol) were added. After 2 h, the mixture was evaporated undervacuum and the residue was loaded directly onto a silica gel column,running with a hexanes-ethyl acetate gradient, and eluting the productat 5% EtOAc. The product was obtained as a colorless oil, 3.7 g, in 85%yield; ¹H NMR (CDCl₃) δ 0.13 (s, 6H), 0.93 (s, 9H), 4.41 (s, 2H), 4.77(s, 2H), 6.29 (s, 1H).

Step 3: tert-Butyl((5-(hydroxymethyl)isoxazol-3-yl)methyl)methyl)carbamate

3-(Bromomethyl)-5-((tert-butyldimethylsilyloxy)methyl)isoxazole (3.7 g,12.08 mmol) was dissolved in Methylamine, 33% wt. solution in absoluteethanol (100 ml, 12.08 mmol) (100 mL), and the mixture was stirred atroom temperature for 1 h, and was then evaporated to dryness. Theresidue was dissolved in THF, and Di-tert butyl dicarbonate (5.80 g,26.6 mmol) and DIEA (6.94 ml, 39.9 mmol) were added. The mixture stirredat ambient temperature for 16 h. Then, 5 mL of pH 7 buffer solution wereadded, and 1 M TBAF in THF (20 mL) were added, and the mixture stirredat ambient temperature for 3 h. Then, the mixture was evaporated undervacuum. The residue was partitioned between EtOAc (75 mL) and water (100mL). The aqueous phase was extracted with EtOAc (75 mL), and thecombined organic layers were washed with water (2×100 mL) and brine (100mL), dried (MgSO₄), and evaporated. This crude product was used directlyas such in the next step, withouth further characterization orpurification.

Step 4: Methyl5-amino-4-(4-((3-(((tert-butoxycarbonyl)methylamino)methyl)isoxazol-5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate

A mixture of methyl5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (1.206 g,4.13 mmol) and tert-butyl(5-(hydroxymethyl)isoxazol-3-yl)methyl(methyl)carbamate (1 g, 4.13 mmol)was cooled to 0° C. Triphenylphosphine, polymer-bound, 3 mmol/g (2.75 g,8.26 mmol) was added, followed by DIAD (1.625 ml, 8.26 mmol). The icebath was allowed to melt, and the mixture stirred at room temperaturefor 16 h. The mixture was filtered and the filtrate was evaporated. Theresidue was dissolved in EtOAc (100 mL) and washed with 10% aqueousNa₂CO₃ (2×100 mL) and water (2×100 mL), and was evaporated. The residuewas chromatographed using a methylene chloride-acetonitrile gradient,eluting the product at 70-80% acetonitrile, and providing 0.50 g wasobtained as an oil, in 24% yield.

Step 5:3-(4-((3-((Methylamino)methyl)isoxazol-5-yl)methoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A solution of methyl5-amino-4-(4-((3-((tert-butoxycarbonyl(methyl)amino)methyl)isoxazol-5-yl)methoxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(0.5 g, 0.968 mmol) in THF (100 mL) was cooled to 0° C., and potassiumtert-butoxide (0.109 g, 0.968 mmol) was added. Stirring proceeded atthis temperature, commencing at t=2:00 PM. After 30 min, the mixture wasquenched with AcOH (5 mL) and was then partitioned between saturatedaqueous NaHCO₃ (100 mL) and EtOAc (100 mL), and the aqueous phase wasextracted with EtOAc (100 mL). The combined organic phases were washedwith saturated aqueous NaHCO₃ (100 mL), water (100 mL), and brine (100mL), were dried (MgSO₄) and evaporated, providing 0.39 g as an oil. Theresidue was dissolved in CH₂Cl₂ (20 mL) with stirring at rt, and 2M HClin Et₂O (4 mL) was added. The mixture was stirred at ambienttemperature, for 16 h. Then, the mixture partitioned between water (50mL) and CH₂Cl₂ (50 mL), and the aqueous phase was made basic using 10%aqueous sodium carbonate solution. The mixture was extracted into EtOAc(3×50 mL), and the combined extracts were dried (MgSO₄) and evaporated.After drying, 160 mg were obtained as a white solid, in 43% yield; mp220-222° C. HPLC: Waters X-Terra, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm,5/95 to 95/5 CH₃CN-0.1% NH₄(HCO₂) over 5 min then 10 min 95/5 CH₃CN-0.1%NH₄(HCO₂): 3.70 (100%). ¹H NMR (DMSO-d₆) δ 1.94-2.04 (m, 1H), 2.26 (s,3H), 2.35-2.47 (m, 1H), 2.58 (d, J=17.8 Hz, 1H), 2.82-3.00 (m, 1H), 3.70(s, 2H), 4.24 (d, J=17.6 Hz, 1H), 4.34-4.47 (m, J=17.6 Hz, 1H), 5.11(dd, J=5.0, 13.1 Hz, 1H), 5.44 (s, 2H), 6.64 (s, 1H), 7.30-7.44 (m, 2H),7.46-7.58 (m, 1H), 10.98 (s, 1H). ¹³C NMR (DMSO-d₆) δ 22.33, 31.20,35.23, 45.02, 45.54, 51.62, 60.72, 103.86, 115.07, 115.96, 129.87,129.94, 133.50, 152.68, 162.90, 166.98, 167.82, 170.94, 172.80. Anal.Calcd for C₁₉H₂₀N₄O₅+0.5H2O: C, 58.01%; H, 5.38%; N, 14.24%; Found: C,58.00%; H, 5.20%; N, 13.90%.

5.3043-(1-OXO-4-((4-((4-(5-(2-OXOHEXAHYDRO-1H-THIENO[3,4-D]IMIDAZOL-4-YL)PENTANOYL)PIPERAZIN-1-YL)METHYL)BENZYL)OXY)ISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: tert-Butyl piperazine-1-carboxylate (0.6 g, 3.2 mmol) andN,N-diisopropylethylamine (9.6 mL, 3.2 mmol) were added to a stirredsolution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.7 g, 1.6 mmol) in CH₂Cl₂ (60 mL). The resulting mixture was stirredat room temperature overnight. The reaction mixture was washed withwater (2×35 mL), brine (35 mL) and dried. Solvent was removed andresidue was purified by chromatography (SiO₂, 3% CH₃OH/CH₂Cl₂ for 15 minthen to 5% over 5 min and hold for 15 min then to 10% over 5 min andhold for 15 min) to give tert-butyl4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)piperazine-1-carboxylate(0.7 g, 83%): ¹H NMR (DMSO-d₆) δ 1.38 (s, 9H), 1.96-2.00 (m, 1H),2.28-2.32 (m, 4H), 2.54-2.60 (m, 2H), 2.87-2.93 (m, 1H), 3.29-3.32 (m,4H), 3.48 (s, 2H), 4.22-4.28 (d, J=18 Hz, 1H), 4.39-4.45 (d, J=18 Hz,1H), 5.08-5.14 (dd, J=6 and 12 Hz, 1H), 5.23 (s, 2H), 7.31-7.51 (m, 7H),10.97 (s, 1H); ¹³C NMR (DMSO-d₆) δ 22.33, 28.00, 31.16, 45.06, 51.55,52.30, 61.59, 69.36, 78.68, 114.94, 115.20, 127.63, 128.94, 129.78,129.92, 133.27, 135.28, 137.72, 153.46, 153.74, 167.99, 170.95, 172.81.

Step 2: 4M HCL/dioxane (0.7 mL, 6.8 mmol) was added to a stirredsolution of tert-butyl4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yloxy)methyl)benzyl)piperazine-1-carboxylate (0.7 g, 1.3 mmol) in 1,4-dioxane (10 mL) andCH₂Cl₂ (10 mL). The resulting mixture was stirred at room temperatureovernight. 4M HCl/dioxane (1 mL) was added and mixture was stirredovernight. Ether (20 mL) was added and solid was collected by filtrationand dried to give3-(1-oxo-4-(4-(piperazine-1-ylmethyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dione(0.7 g, 100%): ¹H NMR (DMSO-d₆) δ 1.97-2.01 (m, 1H), 2.42-2.62 (m, 2H),2.86-2.98 (m, 1H), 3.35-3.37 (m, 8H), 4.25-4.48 (m, 4H), 5.09-5.15 (dd,J=6 and 12 Hz, 1H), 5.29 (s, 2H), 7.35-7.68 (m, 7H), 9.62 (b, 2H), 10.98(s, 1H); ¹³C NMR (DMSO-d₆) δ 22.36, 31.16, 45.06, 47.35, 51.58, 59.00,66.30, 69.00, 114.96, 115.35, 127.83, 129.83, 129.95, 131.50, 133.34,139.00, 153.35, 167.94, 170.96, 172.81.

Step 3:3-(1-Oxo-4-(4-(piperazin-1-ylmethyl)benzyloxy)isoindolin-2-yl)piperidine-2,6-dione(0.7 g, 1.3 mmol) was dissolved in DMF (10 mL). To this solution wasadded triethylamine (0.4 g, 4.0 mmol) and biotin N-hydroxysuccinimideester (0.4 g, 1.3 mmol). The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was concentrated undervacuum and residue was dissolved in CH₂Cl₂ (120 mL). CH₂Cl₂ solution waswashed with water (2×40 mL), brine (40 mL) and dried. Solvent wasremoved and residue was purified by chromatography (SiO₂, 3%CH₃OH/CH₂Cl₂ for 10 min then to 10% over 10 min and hold for 10 min thento 15% over 5 min and hold for 15 min) to give3-(1-oxo-4-((4-((4-(5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperazin-1-yl)methyl)benzyl)oxy)isoindolin-2-yl)piperidine-2,6-dione(0.5 g, 55%): mp 168-170° C.; ¹H NMR (DMSO-d₆) δ 1.35-1.63 (m, 5H),1.98-2.09 (m, 1H), 2.25-2.60 (m, 9H), 2.82-2.85 (m, 2H), 3.05-3.15 (m,1H), 3.37-3.49 (m, 7H), 4.11-4.45 (m, 4H), 5.08-5.14 (dd, J=6 and 15 Hz,1H), 5.23 (s, 2H), 6.35 (s, 1H), 6.42 (s, 1H), 7.32-7.51 (m, 7H), 10.97(s, 1H); ¹³C NMR (DMSO-d₆) δ 22.33, 24.82, 28.06, 28.23, 31.16, 32.04,40.93, 45.07, 51.56, 52.50, 52.90, 55.41, 59.13, 60.98, 61.52, 69.36,114.97, 115.22, 127.64, 128.95, 129.93, 133.28, 135.33, 137.72, 153.48,162.63, 167.99, 170.44, 170.96, 172.83; Calcd for C₃₅H₄₂N₆O₆S+1.0H₂O; C,60.68; H, 6.40; N, 12.13, S, 4.68; Found: C, 60.32; H, 6.16; N, 11.68;S, 5.28.

5.3053-(4-((4-((BIS(3,3,3-TRIFLUOROPROPYL)AMINO)METHYL)BENZYL)OXY)-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE

Step 1: Methyl5-amino-4-(4-((4-((bis(3,3,3-trifluoropropyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate

To a solution of methyl5-amino-4-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(182 mg, 0.383 mmol) in MeCN (5 mL), was addedbis(3,3,3-trifluoropropyl)amine (80 mg, 0.383 mmol) and DIEA (0.100 mL,0.574 mmol). The clear solution was stirred at room temperature for 2 hand then at 70° C. overnight. After 24 h, the reaction was cooled toroom temperature and concentrated in vacuo to give methyl5-amino-4-(4-((4-((bis(3,3,3-trifluoropropyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate

Methyl5-amino-4-(4-((4-((bis(3,3,3-trifluoropropyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoateas an oil. The crude product was used in the next step without furtherpurification, assuming quantitative conversion. LCMS: MH=604, ˜95 area %at 240 nm.

Step 2:3-(4-((4-((Bis(3,3,3-trifluoropropyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

The crude product obtained in step 1, methyl5-amino-4-(4-(4-((bis(3,3,3-trifluoropropyl)amino)methyl)benzyloxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate(231 mg, 0.383 mmol) was dissolved in DMF (5 mL). To the solution wasadded anhydrous K₂CO₃ (159 mg, 1.148 mmol). The mixture stirred for 20 hat 85° C. and then allowed to stand at room temperature overnight. Thereaction mixture was diluted with EtOAc (˜150 mL) and washed with 1N aq.NaHCO₃ (30 mL). The organic layer was washed with water (30 mL) andbrine, dried over Na₂SO₄, and concentrated in vacuo to give a tan oil.The oil was dissolved in DMF (7 mL) and purified using reversed-phasepreparatory HPLC. The product was eluted with an acetonitrile/watergradient (0.1% formic acid in both mobile phases, 30 to 95% MeCN over 20minutes) and fractions were collected by mass trigger. The desiredfractions were combined and concentrated in vacuo until a thick slurrywas obtained. The solid was collected on a fritted funnel, washed withadditional water, and suction dried. Further drying of the solid in avacuum oven at 60° C. provided3-(4-((4-((bis(3,3,3-trifluoropropyl)amino)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dioneas a white solid (57 mg, 26% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 ml/min, 240 nm, 50/50 CH₃CN/0.1% H₃PO₄, 3.77 min (99.9%);mp: 107-109° C.; ¹H NMR (DMSO-d₆) δ 1.88-2.06 (m, 1H, CHH), 2.34-2.49(m, 5H, CH₂, CH₂, CHH), 2.53-2.76 (m, 5H, CH₂, CH₂, CHH), 2.82-3.03 (m,1H, CHH), 3.63 (br. s., 2H, CH₂), 4.26 (d, J=17.6 Hz, 1H, CHH), 4.43 (d,J=17.4 Hz, 1H, CHH), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 5.24 (s, 2H,CH₂), 7.26-7.41 (m, 4H, Ar), 7.41-7.60 (m, 3H, Ar), 10.96 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 22.33, 30.17 (q, J=20.9 Hz, Mo₂), 31.16, 45.07,45.39, 51.58, 56.40, 69.35, 115.01, 115.22, 127.58, 128.62, 128.68,128.92, 129.76, 129.96, 133.30, 153.46, 167.97, 170.93, 172.80. CCF₃ at30.17 ppm appears as doublet. CF₃ is not detected, possibly due tosplitting; LCMS: MH=572; Anal Calcd for C₂₇H₂₇F6N₃O₄+0.6H₂O: C, 55.69;H, 4.88; N, 7.22; Found: C, 55.72; H, 4.83; N, 7.16.

5.3063-{4-[4-(1H-BENZOIMIDAZOL-2-YLSULFANYLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

To the CH₂Cl₂ solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.35 g, 0.790 mmol) was added 1H-benzo[d]imidazole-2-thiol (0.119 g,0.790 mmol) and DIPEA (0.276 ml, 1.579 mmol). The mixture was stirred atroom temperature overnight. The reaction mixture 7545-071-B showedproduct and SM. The mixture was added water and CH₂Cl₂ then extracted.The organic layer was purified on silica gel column eluted with CH₂Cl₂and MeOH to give3-{4-[4-(1H-benzoimidazol-2-ylsulfanylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas a white solid (0.2 g, 49%). Melting point: 160-162° C. LC-MS m/e=513.HPLC Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm,gradient 5/95 to 5/95 CH₃CN/0.1% H₃PO₄ in H₂O during 5 min and stay at95/5 for 5 min: 7.02 min (97%). ¹H NMR (DMSO-d₆) δ 1.81-2.03 (m, 1H,CHH), 2.26-2.47 (m, 1H, CHH), 2.53-2.63 (m, 1H, CHH), 2.82-3.00 (m, 1H,CHH), 4.13-4.47 (m, 2H, CH₂), 4.58 (s, 2H, CH₂), 5.09 (dd, J=5.1, 13.2Hz, 1H, NCH), 5.20 (s, 2H, CH₂), 7.04-7.18 (m, 2H, Ar), 7.26-7.34 (m,2H, AR), 7.37-7.63 (m, 7H, Ar), 10.95 (s, 1H, NH), 12.56 (br. s., 1H,NH); ¹³C NMR (DMSO-d₆) δ 22.30, 31.16, 34.75, 45.06, 51.55, 69.22,114.88, 115.22, 127.86, 128.92, 129.77, 129.95, 133.28, 135.66, 137.57,149.59, 153.41, 167.97, 170.92, 172.80. Anal Calcd for C₂₈H₂₄N₄O₄S, C:63.27%; H: 4.55%; N: 10.54%. Found, C: 62.94%; H: 4.59%; N: 10.40%.

5.3073-[4-(4-{[ETHYL-(2-PHENOXY-ETHYL)-AMINO]-METHYL}-BENZYLOXY)-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL]-PIPERIDINE-2,6-DIONE

To the CH₃CN (10 ml) solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(0.358 g, 0.808 mmol) at room temperature was addedN-ethyl-2-phenoxyethanamine (0.160 g, 0.969 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.267 ml, 1.615 mmol). The resultingsolution was stirred at room temperature for four hours. Solvent wasevaporated and to the residue was added methylene chloride (80 ml). Themixture was washed with water (2×50 ml), brine (50 ml), dried andconcentrated to an oil, which was purified by silica gel column(MeOH/CH₂Cl₂) to give3-[4-(4-{[Ethyl-(2-phenoxy-ethyl)-amino]-methyl}-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dioneas a white solid (0.334 g, 78% yield); mp, 94-96° C. HPLC: WatersSymmetry C-18, 3.9×150 mm, 5 m, 1 mL/min, 240 nm, gradient from 10/90 to90/10 in 5 min, isocratic at 90/10 for 5 min (CH₃CN/0.1% H₃PO₄), 4.72min (96.2%).

¹H NMR (DMSO-d₆) δ 1.01 (t, J=7.0 Hz, 3H, CH₃), 1.91-2.05 (m, 1H, CHH),2.35-2.48 (m, 1H, CHH), 2.52-2.64 (m, 3H, CHH, CH₂), 2.80 (t, J=6.1 Hz,2H, CH₂), 2.84-2.99 (m, 1H, CHH), 3.66 (s, 2H, CH₂), 4.03 (t, J=6.1 Hz,2H, CH₂), 4.19-4.47 (m, 2H, CH₂), 5.11 (dd, J=5.1, 13.2 Hz, 1H, NCH),5.22 (s, 2H, CH₂), 6.84-6.95 (m, 3H, Ar), 7.21-7.29 (m, 2H, Ar),7.30-7.53 (m, 7H, Ar), 10.97 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 11.81,22.36, 31.20, 45.09, 47.42, 51.37, 51.58, 57.50, 65.95, 69.47, 114.38,114.97, 115.20, 120.39, 127.59, 128.61, 129.40, 129.79, 129.94, 133.29,135.00, 139.65, 153.51, 158.40, 168.01, 170.95, 172.82. LC/MS MH=528.Anal Calcd for C₃₁H₃₃N₃O₅ (+0.1H₂O): C, 70.33; H, 6.32; N, 7.94; Found:C, 70.10; H, 6.22; N, 7.83.

5.3083-{4-[4-(2-DIETHYLAMINO-ETHYLSULFANYLMETHYL)-BENZYLOXY]-1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL}-PIPERIDINE-2,6-DIONE

In a 20 mL scint. vial, 2-(diethylamino)ethanethiol hydrochloride (100mg, 0.590 mmol) was added to a solution of3-(4-(4-(bromomethyl)benzyloxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(200 mg, 0.451 mmol) in acetonitrile (5 mL, 96 mmol). All the solidsdissolved with swirling. To the mixture was addedN-ethyl-N-isopropylpropan-2-amine (0.197 mL, 1.128 mmol),tetrabutylammonium bromide (29 mg, 0.09 mmol) and the yellowish solutionwas stirred at room temperature overnight. The crude mixture wasevaporated to an oil, which was purified by preparative HPLC to give3-{4-[4-(2-Diethylamino-ethylsulfanylmethyl)-benzyloxy]-1-oxo-1,3-dihydro-isoindol-2-yl}-piperidine-2,6-dioneas an off-white solid (69 mg, 30% yield); mp, 135-137° C. HPLC (WatersSymmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, isocratic at 23%/77%MeCN/0.1% H₃PO₄): 3.99 min (96.4%). HPLC (LC5 grad): 4.69 min(95.5%). ¹HNMR (DMSO-d₆) δ 0.92 (t, J=7.2 Hz, 6H, 2CH₃), 1.91-2.06 (m, 1H, CHH),2.40-2.48 (m, 5H, CH₂, CH₂, CHH), 2.52-2.64 (m, 3H, CHH, CH₂), 2.83-3.01(m, 1H, CHH), 3.76 (s, 2H, CH₂), 4.21-4.47 (m, 3H, CH₂), 5.11 (dd,J=5.2, 13.3 Hz, 1H, NCH), 5.23 (s, 2H, CH₂), 7.29-7.38 (m, 4H, Ar),7.41-7.53 (m, 3H, Ar), 8.21 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ 11.53,22.38, 28.21, 31.20, 34.96, 45.09, 46.17, 51.58, 52.12, 69.33, 115.00,115.23, 127.77, 128.90, 129.78, 129.95, 133.31, 135.10, 138.67, 153.46,163.65 (from HCOOH), 167.99, 170.95, 172.82. LC/MS m/e=496. Anal Calcdfor C₂₇H₃₃N₃O₄S: C, 65.43; H, 6.71; N, 8.48.

5.309 ASSAYS

5.309.1 TNFα Inhibition Assay in hPMBC

Human peripheral blood mononuclear cells (hPBMC) from normal donors areobtained by Ficoll Hypaque (Pharmacia, Piscataway, N.J., USA) densitycentrifugation. Cells are cultured in RPMI 1640 (Life Technologies,Grand Island, N.Y., USA) supplemented with 10% AB+ human serum (GeminiBio-products, Woodland, Calif., USA), 2 mM L-glutamine, 100 U/mlpenicillin, and 100 μg/ml streptomycin (Life Technologies).

PBMC (2×10⁵ cells) are plated in 96-well flat-bottom Costar tissueculture plates (Corning, N.Y., USA) in triplicate. Cells are stimulatedwith LPS (from Salmonella abortus equi, Sigma cat. no. L-1887, St.Louis, Mo., USA) at 1 ng/ml final in the absence or presence ofcompounds. Compounds provided herein are dissolved in DMSO (Sigma) andfurther dilutions are done in culture medium immediately before use. Thefinal DMSO concentration in all assays can be about 0.25%. Compounds areadded to cells 1 hour before LPS stimulation. Cells are then incubatedfor 18-20 hours at 37° C. in 5% CO₂, and supernatants are thencollected, diluted with culture medium and assayed for TNFα levels byELISA (Endogen, Boston, Mass., USA). IC₅₀s are calculated usingnon-linear regression, sigmoidal dose-response, constraining the top to100% and bottom to 0%, allowing variable slope (GraphPad Prism v3.02).

5.309.2 IL-2 and MIP-3a Production by T Cells

PBMC are depleted of adherent monocytes by placing 1×10⁸ PBMC in 10 mlcomplete medium (RPMI 1640 supplemented with 10% heat-inactivated fetalbovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/mlstreptomycin) per 10 cm tissue culture dish, in 37° C., 5% CO₂ incubatorfor 30-60 minutes. The dish is rinsed with medium to remove allnon-adherent PBMC. T cells are purified by negative selection using thefollowing antibody (Pharmingen) and Dynabead (Dynal) mixture for every1×108 non-adherent PBMC: 0.3 ml Sheep anti-mouse IgG beads, 15 μlanti-CD16, 15 μl anti-CD33, 15 μl anti-CD56, 0.23 ml anti-CD19 beads,0.23 ml anti-HLA class II beads, and 56 μl anti-CD14 beads. The cellsand bead/antibody mixture is rotated end-over-end for 30-60 minutes at4° C. Purified T cells are removed from beads using a Dynal magnet.Typical yield is about 50% T cells, 87-95% CD3⁺ by flow cytometry.

Tissue culture 96-well flat-bottom plates are coated with anti-CD3antibody OKT3 at 5 μg/ml in PBS, 100 μl per well, incubated at 37° C.for 3-6 hours, then washed four times with complete medium 100 μl/welljust before T cells are added. Compounds are diluted to 20 times offinal in a round bottom tissue culture 96-well plate. Finalconcentrations are about 10 μM to about 0.00064 μM. A 10 mM stock ofcompounds provided herein is diluted 1:50 in complete for the first 20×dilution of 200 μM in 2% DMSO and serially diluted 1:5 into 2% DMSO.Compound is added at 10 μl per 200 μl culture, to give a final DMSOconcentration of 0.1%. Cultures are incubated at 37° C., 5% CO₂ for 2-3days, and supernatants analyzed for IL-2 and MIP-3a by ELISA (R&DSystems). IL-2 and MIP-3a levels are normalized to the amount producedin the presence of an amount of a compound provided herein, and EC₅₀scalculated using non-linear regression, sigmoidal dose-response,constraining the top to 100% and bottom to 0%, allowing variable slope(GraphPad Prism v3.02).

5.309.3 Cell Proliferation Assay

Cell lines (e.g., Namalwa, MUTZ-5, UT-7, and various NHL cell lines) areobtained from the Deutsche Sammlung von Mikroorganismen und ZellkulturenGmbH (Braunschweig, Germany). The cell line KG-1 is obtained from theAmerican Type Culture Collection (Manassas, Va., USA). Cellproliferation as indicated by ³H-thymidine incorporation is measured inall cell lines as follows.

Cells are plated in 96-well plates at 6000 cells per well in media. Thecells are pre-treated with compounds at about 100, 10, 1, 0.1, 0.01,0.001, 0.0001 and 0 μM in a final concentration of about 0.25% DMSO intriplicate at 37° C. in a humidified incubator at 5% CO₂ for 72 hours.One microcurie of ³H-thymidine (Amersham) is then added to each well,and cells are incubated again at 37° C. in a humidified incubator at 5%CO₂ for 6 hours. The cells are harvested onto UniFilter GF/C filterplates (Perkin Elmer) using a cell harvester (Tomtec), and the platesare allowed to dry overnight. Microscint 20 (Packard) (25 μl/well) isadded, and plates are analyzed in TopCount NXT (Packard). Each well iscounted for one minute. Percent inhibition of cell proliferation iscalculated by averaging all triplicates and normalizing to the DMSOcontrol (0% inhibition). Each compound is tested in each cell line inthree separate experiments. Final IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope. (GraphPad Prism v3.02).

5.309.4 Immunoprecipitation and Immunoblot

Cells (e.g., various NHL cell lines) are treated with DMSO or an amountof a compound provided herein for 1 hour, then stimulated with 10 U/mlof Epo (R&D Systems) for 30 minutes. Cell lysates are prepared andeither immunoprecipitated with Epo receptor Ab or separated immediatelyby SDS-PAGE. Immunoblots are probed with Akt, phospo-Akt (Ser473 orThr308), phospho-Gab1 (Y627), Gab1, IRS2, actin and IRF-1 Abs andanalyzed on a Storm 860 Imager using ImageQuant software (MolecularDynamics).

5.309.5 Cell Cycle Analysis

Cells are treated with DMSO or an amount of a compound provided hereinovernight. Propidium iodide staining for cell cycle is performed usingCycleTEST PLUS (Becton Dickinson) according to manufacturer's protocol.Following staining, cells are analyzed by a FACSCalibur flow cytometerusing ModFit LT software (Becton Dickinson).

5.309.6 Apoptosis Analysis

Cells are treated with DMSO or an amount of a compound provided hereinat various time points, then washed with annexin-V wash buffer (BDBiosciences). Cells are incubated with annexin-V binding protein andpropidium iodide (BD Biosciences) for 10 minutes. Samples are analyzedusing flow cytometry.

5.309.7 Luciferase Assay

Namalwa cells are transfected with 4 μg of API-luciferase (Stratagene)per 1×10⁶ cells and 3 μl Lipofectamine 2000 (Invitrogen) reagentaccording to manufacturer's instructions. Six hours post-transfection,cells are treated with DMSO or an amount of a compound provided herein.Luciferase activity is assayed using luciferase lysis buffer andsubstrate (Promega) and measured using a luminometer (Turner Designs).

5.309.8 TNFα Inhibition

Using procedures substantially similar to those provided in Section5.309.1 above, IC₅₀ values for certain of the compounds provided hereinfor TNFα inhibition were determined. Tested compounds include thecompounds of Examples 5.2, 5.6-5.24, 5.29-5.46, 5.48-5.69, 5.71-5.133,5.136-5.143, 5.151-5.155, 5.158-5.188, 5.193-5.201, 5.207, 5.224-5.289,5.293-5.296 and 5.299-5.308.

The determined IC₅₀ values ranged from about 0.02 nM to about 2 μM.These results show that compounds provided herein are useful asinhibitors of TNFα.

5.309.9 IL-2 Production

Using procedures substantially similar to those described in Section5.309.2. above, EC₅₀ values of certain compounds provided herein for theproduction of IL-2 were also determined. Tested compounds include thecompounds of Examples 5.2, 5.6-5.24, 5.30-5.46, 5.48-5.57, 5.59-5.69,5.71-5.133, 5.136-5.137, 5.139-5.143, 5.151-5.188, 5.194-5.201, 5.207,5.216-5.289, 5.293-5.296, 5.300 and 5.303-5.308.

The determined EC₅₀ values ranged from about 0.01 nM to about 1.4 μM.These results show that compounds provided herein are useful asstimulators of IL-2 production.

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the claimed subject matter and areencompassed by the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein in their entireties. Citation oridentification of any reference in this application is not an admissionthat such reference is available as prior art to the claimed subjectmatter. The full scope of the invention is better understood withreference to the appended claims.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein: X is C═O or CH₂; R¹ is —Y—R³; R² is H or (C₁-C₆)alkyl; Y is: 6to 10 membered aryl, heteroaryl or heterocycle, each of which may beoptionally substituted with one or more halogen; or a bond; R³ is:—(CH₂)_(n)-aryl, —O—(CH₂)_(n)-aryl or —(CH₂)_(n)—O-aryl, wherein thearyl is optionally substituted with one or more: (C₁-C₆)alkyl, itselfoptionally substituted with one or more halogen; (C₁-C₆)alkoxy, itselfsubstituted with one or more halogen; oxo; amino; carboxyl; cyano;hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl,optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkoxy orhalogen; —CONH₂; or —COO—(C₁-C₆)alkyl, wherein the alkyl may beoptionally substituted with one or more halogen; —(CH₂)_(n)-heterocycle,—O—(CH₂)_(n)-heterocycle or —(CH₂)_(n)—O-heterocycle, wherein theheterocycle is optionally substituted with one or more: (C₁-C₆)alkyl,itself optionally substituted with one or more halogen; (C₁-C₆)alkoxy,itself substituted with one or more halogen; oxo; amino; carboxyl;cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl orheteroaryl, optionally substituted with one or more (C₁-C₆)alkyl,(C₁-C₆)alkoxy or halogen; —CONH₂; or —COO—(C₁-C₆)alkyl, wherein thealkyl may be optionally substituted with one or more halogen; or—(CH₂)_(n)-heteroaryl, —O—(CH₂)_(n)-heteroaryl or—(CH₂)_(n)—O-heteroaryl, wherein the heteroaryl is optionallysubstituted with one or more: (C₁-C₆)alkyl, itself optionallysubstituted with one or more halogen; (C₁-C₆)alkoxy, itself substitutedwith one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl;halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionallysubstituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkoxy or halogen;—CONH₂; or —COO—(C₁-C₆)alkyl, wherein the alkyl may be optionallysubstituted with one or more halogen; and n is 0, 1,2 or
 3. 2. Thecompound of claim 1, wherein X is CH₂.
 3. The compound of claim 1,wherein Y is phenyl, and R³ is —(CH₂)_(n)-heterocycle.
 4. The compoundof claim 1, wherein Y is heteroaryl, and R³ is —(CH₂)_(n)-heterocycle.5. The compound of claim 1, wherein Y is a bond.
 6. The compound ofclaim 1, wherein Y is a bond, and R³ is —(CH₂)_(n)-heterocycle or—(CH₂)_(n)-heteroaryl.
 7. The compound of claim 1, which is:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.8. A compound of formula (II):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein: R⁴ is unsubstituted 9 to 10 membered bicyclic ring isbenzothiazole, quinoline, isoquinoline, naphthalene,2,3-dihydro-1H-indene, benzo[d][1,2,3]triazole, imidazo[1,2-a]pyridine,benzofuran, 2,3-dihydrobenzofuran, benzothiophene, benzo[d]oxazoleisoindoline or chroman; with the proviso that if the bicyclic ring isbenzofuran or benzothiophene, then the ring is not connected to theisoindole ring through the 2-position.
 9. The compound of claim 8, whichis:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.10. A compound of formula (III):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein: X is CH₂ or C═O; R⁵, R⁶ and R⁷ are each independently hydrogen,halogen, nitro, carbamoyl, amino, —SO₂R⁸, —CONR⁹R¹⁰, —(C₁-C₆)alkyl or—(C₁-C₆)alkoxy, said alkyl or alkoxy may be optionally substituted withone or more halogen, amino, hydroxyl, or NR⁹R¹⁰; R⁸ is: (C₁-C₆)alkyl,optionally substituted with (C₁-C₆)alkyl or (C₆-C₁₀)aryl; amino,optionally substituted with (C₁-C₆)alkyl or (C₆-C₁₀)aryl; or 6 to 10membered heterocycle, optionally substituted with (C₁-C₆)alkyl or(C₆-C₁₀)aryl; R⁹ and R¹⁰ are each independently hydrogen, 6 to 10membered aryl, —COO—(C₁-C₆)alkyl, —(C₀-C₆)alkyl-CHO, —(C₀-C₆)alkyl-COOH,—(C₀-C₆)alkyl-NR⁹R¹⁰, —(C₀-C₆)alkyl-(5 to 10 membered heterocycle),—(C₁-C₆)alkyl-OH, —(C₁-C₆)alkyl-O-(C₁-C₆)alkyl, (C₁-C₆)alkyl, or(C₃-C₆)cycloalkyl; or R⁹ and R¹⁰ together may form an optionallysubstituted 5 to 6 membered ring containing one or more heteroatoms; andR^(9′) and R^(10′) are each independently hydrogen or (C₁-C₆)alkyl; withthe proviso that all of R⁵-R⁷ cannot be hydrogen; and with the provisothat if one of R⁵-R⁷ is hydrogen and the remaining two of R⁵-R⁷ are bothchloride, then the two chloride atoms cannot be on 3 and 4 position ofthe phenyl ring.
 11. The compound of claim 10, wherein one of R⁵-R⁷ ishydrogen, and the remaining two of R⁵-R⁷ are each independently halogen,(C₁-C₆)alkoxy or (C₁-C₆)alkyl.
 12. The compound of claim 10, wherein twoof R⁵-R⁷ are hydrogen and the remaining one of R⁵-R⁷ is halogen,(C₁-C₆)alkoxy or (C₁-C₆)alkyl.
 13. The compound of claim 10, which is:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.14. A compound of formula (IV):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof,wherein: X is N or C; Y is CH₂ or C═O; R¹¹ and R¹² are eachindependently hydrogen, —(C₁-C₆)alkyl, —(C₁-C₆)alkyl-(C₃-C₆)cycloalkyl,—(C₁-C₆)alkoxy, —(C₆-C₁₀)aryl, —CO(C₁-C₆)alkyl, —CO(C₃-C₆)cycloalkyl,—CO(C₆-C₁₀)aryl, —COO(C₁-C₆)alkyl, halogen, hydroxyl, oxo, 3 to 10membered heterocycle, 6 to 10 membered heteroaryl, —NHCO(C₁-C₆)alkyl,—(CH₂)_(n)-phenyl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl,—SO₂(C₆-C₁₀)aryl or —NR¹⁴R¹⁵, wherein the alkyl, aryl or heteroarylportion of each of the groups may be optionally substituted with one ormore halogen, hydroxyl or —(C₁-C₆)alkoxy; R¹³ is hydrogen or—(C₁-C₆)alkyl; R¹⁴ and R¹⁵ are each independently hydrogen or—(C₁-C₆)alkyl; and n is 0, 1, 2 or
 3. 15. The compound of claim 14,wherein X is N.
 16. The compound of claim 14, wherein Y is CH₂.
 17. Thecompound of claim 14, which is:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.18. A compound, which is:

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.19. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof. 20.A pharmaceutical composition comprising a compound of claim 8, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof. 21.A pharmaceutical composition comprising a compound of claim 10, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof. 22.A pharmaceutical composition comprising a compound of claim 14, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof. 23.A pharmaceutical composition comprising a compound of claim 18, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof.